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1.
Hum Mutat ; 41(3): 543-580, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31898847

RESUMO

Hermansky-Pudlak syndrome (HPS) is a group of 10 autosomal recessive multisystem disorders, each defined by the deficiency of a specific gene. HPS-associated genes encode components of four ubiquitously expressed protein complexes: Adaptor protein-3 (AP-3) and biogenesis of lysosome-related organelles complex-1 (BLOC-1) through -3. All individuals with HPS exhibit albinism and a bleeding diathesis; additional features occur depending on the defective protein complex. Pulmonary fibrosis is associated with AP-3 and BLOC-3 deficiency, immunodeficiency with AP-3 defects, and gastrointestinal symptoms are more prevalent and severe in BLOC-3 deficiency. Therefore, identification of the HPS subtype is valuable for prognosis, clinical management, and treatment options. The prevalence of HPS is estimated at 1-9 per 1,000,000. Here we summarize 264 reported and novel variants in 10 HPS genes and estimate that ~333 Puerto Rican HPS subjects and ~385 with other ethnicities are reported to date. We provide pathogenicity predictions for missense and splice site variants and list variants with high minor allele frequencies. Current cellular and clinical aspects of HPS are also summarized. This review can serve as a manifest for molecular diagnostics and genetic counseling aspects of HPS.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Síndrome de Hermanski-Pudlak/diagnóstico , Síndrome de Hermanski-Pudlak/genética , Mutação , Alelos , Estudos de Associação Genética/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Família Multigênica , Fenótipo
2.
Clin J Am Soc Nephrol ; 12(12): 1962-1973, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29146704

RESUMO

BACKGROUND AND OBJECTIVES: Joubert syndrome is a genetically heterogeneous ciliopathy associated with >30 genes. The characteristics of kidney disease and genotype-phenotype correlations have not been evaluated in a large cohort at a single center. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated 97 individuals with Joubert syndrome at the National Institutes of Health Clinical Center using abdominal ultrasonography, blood and urine chemistries, and DNA sequencing. RESULTS: Patients were ages 0.6-36 years old (mean of 9.0±7.6 years old); 41 were female. Mutations were identified in 19 genes in 92 patients; two thirds of the mutations resided in six genes: TMEM67, C5orf42, CC2D2A, CEP290, AHI1, and KIAA0586. Kidney disease was detected in 30%, most commonly in association with the following genes: CEP290 (six of six), TMEM67 (11 of 22), and AHI1 (three of six). No kidney disease was identified in patients with mutations in C5orf42 (zero of 15) or KIAA0586 (zero of six). Prenatal ultrasonography of kidneys was normal in 72% of patients with kidney disease. Specific types of kidney disease included nephronophthisis (31%), an overlap phenotype of autosomal recessive polycystic kidney disease/nephronophthisis (35%), unilateral multicystic dysplastic kidney (10%), and indeterminate-type cystic kidney disease (24%). Early-onset hypertension occurred in 24% of patients with kidney disease. Age at ESRD (n=13) ranged from 6 to 24 years old (mean of 11.3±4.8 years old). CONCLUSIONS: Kidney disease occurs in up to one third of patients with Joubert syndrome, most commonly in those with mutations in CEP290, TMEM67, and AHI1. Patients with mutations in C5orf42 or KIAA0586 are less likely to develop kidney disease. Prenatal ultrasonography is a poor predictor of kidney involvement in Joubert syndrome. Unilateral multicystic dysplastic kidney and autosomal recessive polycystic kidney disease-like enlarged kidneys with early-onset hypertension can be part of the Joubert syndrome kidney phenotype.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Cerebelo/anormalidades , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Doenças Renais Císticas/congênito , Falência Renal Crônica/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transporte Vesicular , Adolescente , Adulto , Idade de Início , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Cerebelo/diagnóstico por imagem , Cerebelo/metabolismo , Criança , Pré-Escolar , Proteínas do Citoesqueleto , Anormalidades do Olho/complicações , Anormalidades do Olho/diagnóstico por imagem , Feminino , Genótipo , Humanos , Lactente , Doenças Renais Císticas/complicações , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Falência Renal Crônica/etiologia , Imageamento por Ressonância Magnética , Masculino , Proteínas de Membrana/genética , Rim Displásico Multicístico/complicações , Rim Displásico Multicístico/diagnóstico por imagem , Rim Displásico Multicístico/genética , Mutação , Proteínas de Neoplasias/genética , Fenótipo , Rim Policístico Autossômico Recessivo/complicações , Rim Policístico Autossômico Recessivo/diagnóstico por imagem , Rim Policístico Autossômico Recessivo/genética , Estudos Prospectivos , Proteínas/genética , Retina/diagnóstico por imagem , Retina/metabolismo , Ultrassonografia Pré-Natal , Adulto Jovem
3.
Front Med (Lausanne) ; 4: 62, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28603714

RESUMO

Traditionally, the use of genomic information for personalized medical decisions relies on prior discovery and validation of genotype-phenotype associations. This approach constrains care for patients presenting with undescribed problems. The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) hypothesized that defining disease as maladaptation to an ecological niche allows delineation of a logical framework to diagnose and evaluate such patients. Herein, we present the philosophical bases, methodologies, and processes implemented by the NIH UDP. The NIH UDP incorporated use of the Human Phenotype Ontology, developed a genomic alignment strategy cognizant of parental genotypes, pursued agnostic biochemical analyses, implemented functional validation, and established virtual villages of global experts. This systematic approach provided a foundation for the diagnostic or non-diagnostic answers provided to patients and serves as a paradigm for scalable translational research.

4.
Hum Genet ; 136(4): 399-408, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28220259

RESUMO

Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic "molar tooth sign" on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients' fibroblasts.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Hormônio do Crescimento/deficiência , Doenças Renais Císticas/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Sequência de Aminoácidos , Animais , Cerebelo/diagnóstico por imagem , Criança , Anormalidades do Olho/diagnóstico por imagem , Feminino , Humanos , Doenças Renais Císticas/diagnóstico por imagem , Masculino , Retina/diagnóstico por imagem , Homologia de Sequência de Aminoácidos
5.
Hum Genet ; 136(4): 409-420, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28213671

RESUMO

Smith-Magenis syndrome (SMS), a neurodevelopmental disorder characterized by dysmorphic features, intellectual disability (ID), and sleep disturbances, results from a 17p11.2 microdeletion or a mutation in the RAI1 gene. We performed exome sequencing on 6 patients with SMS-like phenotypes but without chromosomal abnormalities or RAI1 variants. We identified pathogenic de novo variants in two cases, a nonsense variant in IQSEC2 and a missense variant in the SAND domain of DEAF1, and candidate de novo missense variants in an additional two cases. One candidate variant was located in an alpha helix of Necdin (NDN), phased to the paternally inherited allele. NDN is maternally imprinted within the 15q11.2 Prader-Willi Syndrome (PWS) region. This can help clarify NDN's role in the PWS phenotype. No definitive pathogenic gene variants were detected in the remaining SMS-like cases, but we report our findings for future comparison. This study provides information about the inheritance pattern and recurrence risk for patients with identified variants and demonstrates clinical and genetic overlap of neurodevelopmental disorders. Identification and characterization of ID-related genes that assist in development of common developmental pathways and/or gene-networks, may inform disease mechanism and treatment strategies.


Assuntos
Exoma , Síndrome de Smith-Magenis/genética , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Pré-Escolar , Estudos de Coortes , Proteínas de Ligação a DNA , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Masculino , Proteínas Nucleares/genética , Homologia de Sequência de Aminoácidos , Transativadores , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética
6.
Am J Med Genet A ; 173(3): 661-666, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28052552

RESUMO

Joubert syndrome is a ciliopathy characterized by a specific constellation of central nervous system malformations that result in the pathognomonic "molar tooth sign" on imaging. More than 27 genes are associated with Joubert syndrome, but some patients do not have mutations in any of these genes. Celsr1, Celsr2, and Celsr3 are the mammalian orthologues of the drosophila planar cell polarity protein, flamingo; they play important roles in neural development, including axon guidance, neuronal migration, and cilium polarity. Here, we report bi-allelic mutations in CELSR2 in a Joubert patient with cortical heterotopia, microophthalmia, and growth hormone deficiency. © 2017 Wiley Periodicals, Inc.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Caderinas/genética , Cerebelo/anormalidades , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Hormônio do Crescimento Humano/deficiência , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Microftalmia/genética , Mutação , Retina/anormalidades , Alelos , Caderinas/química , Criança , Fácies , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imageamento por Ressonância Magnética , Modelos Moleculares , Polimorfismo de Nucleotídeo Único , Conformação Proteica
7.
Hum Mutat ; 37(11): 1144-1148, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27449316

RESUMO

Joubert and Meckel-Gruber syndromes (JS and MGS) are ciliopathies with overlapping features. JS patients manifest the "molar tooth sign" on brain imaging and variable eye, kidney, and liver disease. MGS presents with polycystic kidneys, occipital encephalocele, and polydactyly; it is typically perinatally fatal. Both syndromes are genetically heterogeneous; some genes cause either syndrome. Here, we report two brothers married to unrelated women. The first brother had three daughters with JS and a son with polycystic kidneys who died at birth. The second brother's wife had a fetal demise due to MGS. Whole exome sequencing identified TMEM231 NM_001077416.2: c.784G>A; p.(Asp262Asn) in all children and the wife of the first brother; the second brother's wife had a c.406T>G;p.(Trp136Gly) change. In-depth analysis uncovered a rare gene conversion event in TMEM231, leading to loss of exon 4, in all the affected children of first brother. We believe that the combination of this gene conversion with different missense mutations led to a spectrum of phenotypes that span JS and MGS.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Transtornos da Motilidade Ciliar/genética , Encefalocele/genética , Anormalidades do Olho/genética , Conversão Gênica , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Doenças Renais Policísticas/genética , Retina/anormalidades , Exoma , Feminino , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Retinose Pigmentar , Análise de Sequência de DNA/métodos
8.
J Med Genet ; 53(5): 318-29, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27095636

RESUMO

BACKGROUND: Laminins are heterotrimeric complexes, consisting of α, ß and γ subunits that form a major component of basement membranes and extracellular matrix. Laminin complexes have different, but often overlapping, distributions and functions. METHODS: Under our clinical protocol, NCT00068224, we have performed extensive clinical and neuropsychiatric phenotyping, neuroimaging and molecular analysis in patients with laminin α1 (LAMA1)-associated lamininopathy. We investigated the consequence of mutations in LAMA1 using patient-derived fibroblasts and neuronal cells derived from neuronal stem cells. RESULTS: In this paper we describe individuals with biallelic mutations in LAMA1, all of whom had the cerebellar dysplasia, myopia and retinal dystrophy, in addition to obsessive compulsive traits, tics and anxiety. Patient-derived fibroblasts have impaired adhesion, reduced migration, abnormal morphology and increased apoptosis due to impaired activation of Cdc42, a member of the Rho family of GTPases that is involved in cytoskeletal dynamics. LAMA1 knockdown in human neuronal cells also showed abnormal morphology and filopodia formation, supporting the importance of LAMA1 in neuronal migration, and marking these cells potentially useful tools for disease modelling and therapeutic target discovery. CONCLUSION: This paper broadens the phenotypes associated with LAMA1 mutations. We demonstrate that LAMA1 deficiency can lead to alteration in cytoskeletal dynamics, which may invariably lead to alteration in dendrite growth and axonal formation. Estimation of disease prevalence based on population studies in LAMA1 reveals a prevalence of 1-20 in 1 000 000. TRIAL REGISTRATION NUMBER: NCT00068224.


Assuntos
Doenças Cerebelares/metabolismo , Laminina/genética , Mutação , Miopia/metabolismo , Transtorno Obsessivo-Compulsivo/metabolismo , Adulto , Adesão Celular , Movimento Celular , Doenças Cerebelares/genética , Doenças Cerebelares/fisiopatologia , Criança , Feminino , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Humanos , Masculino , Miopia/genética , Miopia/fisiopatologia , Neurônios/metabolismo , Neurônios/fisiologia , Transtorno Obsessivo-Compulsivo/genética , Transtorno Obsessivo-Compulsivo/fisiopatologia , Linhagem , Distrofias Retinianas/genética , Distrofias Retinianas/metabolismo , Distrofias Retinianas/fisiopatologia , Síndrome , Transtornos de Tique/genética , Transtornos de Tique/metabolismo , Transtornos de Tique/fisiopatologia , Adulto Jovem , Proteína cdc42 de Ligação ao GTP
9.
J Med Genet ; 52(12): 830-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26386044

RESUMO

BACKGROUND: In chicken, loss of TALPID3 results in non-functional cilia and short-rib polydactyly syndrome. This phenotype is caused by a frameshift mutation in the chicken ortholog of the human KIAA0586 gene, which encodes a novel coiled-coil domain protein essential for primary ciliogenesis, suggesting that KIAA0586 can be associated with ciliopathy in human beings. METHODS: In our patients with ciliopathy (http://www.clinicaltrials.gov: NCT00068224), we have collected extensive clinical and neuroimaging data from affected individuals, and performed whole exome sequencing on DNA from affected individuals and their parents. We analysed gene expression on fibroblast cell line, and determined the effect of gene mutation on ciliogenesis in cells derived from patients. RESULTS: We identified biallelic mutations in the human TALPID3 ortholog, KIAA0586, in six children with findings of overlapping Jeune and Joubert syndromes. Fibroblasts cultured from one of the patients with Jeune-Joubert syndrome exhibited more severe cilia defects than fibroblasts from patients with only Joubert syndrome; this difference was reflected in KIAA0586 RNA expression levels. Rescue of the cilia defect with full-length wild type KIAA0586 indicated a causal link between cilia formation and KIAA0586 function. CONCLUSIONS: Our results show that biallelic deleterious mutations in KIAA0586 lead to Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Furthermore, our results confirm that KIAA0586/TALPID3 is essential in cilia formation in human beings, expand the KIAA0586 phenotype to include features of Jeune syndrome and provide a pathogenetic connection between Joubert and Jeune syndromes, based on aberrant ciliogenesis.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Síndrome de Ellis-Van Creveld/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Retina/anormalidades , Animais , Sequência de Bases , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Galinhas/genética , Criança , Pré-Escolar , Cílios/patologia , Análise Mutacional de DNA , Feminino , Fibroblastos/patologia , Mutação da Fase de Leitura , Expressão Gênica , Humanos , Masculino , Linhagem , Cultura Primária de Células
10.
Mol Genet Metab ; 114(3): 474-82, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25577287

RESUMO

Store-operated Ca(2+) entry is the major route of replenishment of intracellular Ca(2+) in animal cells in response to the depletion of Ca(2+) stores in the endoplasmic reticulum. It is primarily mediated by the Ca(2+)-selective release-activated Ca(2+) (CRAC) channel, which consists of the pore-forming subunits ORAI1-3 and the Ca(2+) sensors, STIM1 and STIM2. Recessive loss-of-function mutations in STIM1 or ORAI1 result in immune deficiency and nonprogressive myopathy. Heterozygous gain-of-function mutations in STIM1 cause non-syndromic myopathies as well as syndromic forms of miosis and myopathy with tubular aggregates and Stormorken syndrome; some of these syndromic forms are associated with thrombocytopenia. Increased concentration of Ca(2+) as a result of store-operated Ca(2+) entry is essential for platelet activation. The York Platelet syndrome (YPS) is characterized by thrombocytopenia, striking ultrastructural platelet abnormalities including giant electron-opaque organelles and massive, multilayered target bodies and deficiency of platelet Ca(2+) storage in delta granules. We present clinical and molecular findings in 7 YPS patients from 4 families, demonstrating that YPS patients have a chronic myopathy associated with rimmed vacuoles and heterozygous gain-of-function STIM1 mutations. These findings expand the phenotypic spectrum of STIM1-related human disorders and define the molecular basis of YPS.


Assuntos
Plaquetas/patologia , Canalopatias/genética , Proteínas de Membrana/genética , Doenças Musculares/genética , Proteínas de Neoplasias/genética , Adulto , Transtornos Plaquetários/genética , Transtornos Plaquetários/metabolismo , Plaquetas/fisiologia , Plaquetas/ultraestrutura , Cálcio/metabolismo , Criança , Pré-Escolar , Dislexia/genética , Dislexia/metabolismo , Eritrócitos Anormais/metabolismo , Exoma/genética , Feminino , Heterozigoto , Humanos , Ictiose/genética , Ictiose/metabolismo , Lactente , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/metabolismo , Miose/genética , Miose/metabolismo , Fadiga Muscular/genética , Doenças Musculares/metabolismo , Mutação , Linhagem , Análise de Sequência de DNA , Baço/anormalidades , Baço/metabolismo , Molécula 1 de Interação Estromal , Trombocitopenia
11.
Arch Gynecol Obstet ; 291(3): 705-8, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25214022

RESUMO

PURPOSE: Autosomal recessive polycystic kidney disease (ARPKD) is the most common childhood-onset ciliopathy. As treatments improve, more women are reaching reproductive age, but little is known about ARPKD and pregnancy. METHODS: In our ongoing study on ARPKD and other ciliopathies, 12 females over 18 years of age were identified and systematically evaluated. Six had children; four carried pregnancies and delivered, one used assisted reproductive technology and had a surrogate carry the pregnancy, and one adopted. We report the outcomes of four pregnancies with live birth deliveries and two women who chose alternate family building options. RESULTS: Patient one was diagnosed at 6 months, and at age 21 had a pregnancy complicated by transient worsening of renal function (creatinine increase from 1.15 to 1.78 mg/dL). Patient two was diagnosed with ARPKD at age seven and had an uncomplicated pregnancy at age 23. Patient three was diagnosed incidentally with ARPKD at age 23, 3 months after completion of an uncomplicated pregnancy. Patient four who had an uncomplicated pregnancy at age 33 was diagnosed with ARPKD at age 46. CONCLUSIONS: Women with ARPKD face reproductive decisions largely bereft of information about the pregnancies of other ARPKD patients. We report four cases of pregnancy and ARPKD to expand current knowledge and encourage further research.


Assuntos
Rim Policístico Autossômico Recessivo/complicações , Complicações na Gravidez/etiologia , Adulto , Criança , Feminino , Humanos , Pessoa de Meia-Idade , Gravidez , Resultado da Gravidez
12.
Am J Respir Crit Care Med ; 190(12): 1395-401, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25347450

RESUMO

RATIONALE: The rate of progression of most interstitial lung diseases (ILD) is unpredictable. Fibrocytes are circulating bone marrow-derived cells that have been implicated in the pathogenesis of lung fibrosis. Hermansky-Pudlak syndrome (HPS), a genetic cause of ILD in early adulthood, allows for study of biomarkers of ILD in a homogeneous population at near-certain risk of developing fibrotic lung disease. OBJECTIVES: To test the hypothesis that, in subjects with HPS, the number or phenotype of circulating fibrocytes predicts progression and outcome of ILD. METHODS: We measured circulating fibrocyte counts and chemokine levels in a cohort of subjects with HPS and healthy control subjects and correlated the results to disease outcome. MEASUREMENTS AND MAIN RESULTS: In a cross-sectional analysis, peripheral blood fibrocyte concentrations were markedly elevated in a subset of subjects with HPS who had ILD but not subjects without lung disease or normal control subjects. The blood concentration of fibrocytes expressing the chemokine receptor CXCR4 correlated significantly with the plasma concentration of the CXCR4 ligand, CXCL12. In a longitudinal study, we found marked episodic elevations in circulating fibrocyte counts over a median follow-up period of 614 days. Elevations in both maximal values and final values of peripheral blood CXCR4(+) fibrocyte concentration were strongly associated with death from ILD. CONCLUSIONS: CXCR4(+) fibrocyte concentration may be useful as a biomarker for outcome of ILD in subjects with HPS.


Assuntos
Síndrome de Hermanski-Pudlak/diagnóstico , Células-Tronco Mesenquimais/fisiologia , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Feminino , Síndrome de Hermanski-Pudlak/sangue , Síndrome de Hermanski-Pudlak/mortalidade , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptores CXCR4/sangue , Receptores CXCR4/fisiologia , Análise de Sobrevida
13.
Hum Mutat ; 34(6): 827-35, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23504663

RESUMO

Oculocutaneous albinism (OCA) is a rare genetic disorder of melanin synthesis that results in hypopigmented hair, skin, and eyes. There are four types of OCA caused by mutations in TYR (OCA-1), OCA2 (OCA-2), TYRP1 (OCA-3), or SLC45A2 (OCA-4). Here we report 22 novel mutations in the OCA genes; 14 from a cohort of 61 patients seen as part of the NIH OCA Natural History Study and eight from a prior study at the University of Minnesota. We also include a comprehensive list of almost 600 previously reported OCA mutations along with ethnicity information, carrier frequencies, and in silico pathogenicity predictions as a supplement. In addition to discussing the clinical and molecular features of OCA, we address the cases of apparent missing heritability. In our cohort, 26% of patients did not have two mutations in a single OCA gene. We demonstrate the utility of multiple detection methods to reveal mutations missed by Sanger sequencing. Finally, we review the TYR p.R402Q temperature-sensitive variant and confirm its association with cases of albinism with only one identifiable TYR mutation.


Assuntos
Albinismo Oculocutâneo/diagnóstico , Albinismo Oculocutâneo/genética , Mutação , Albinismo Oculocutâneo/epidemiologia , Antígenos de Neoplasias/química , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Estudos de Associação Genética , Variação Genética , Genótipo , Humanos , Padrões de Herança , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Monofenol Mono-Oxigenase/química , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/metabolismo , Oxirredutases/química , Oxirredutases/genética , Oxirredutases/metabolismo , Fenótipo , Prevalência , Relação Estrutura-Atividade
14.
Gastroenterology ; 144(1): 112-121.e2, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23041322

RESUMO

BACKGROUND & AIMS: Autosomal recessive polycystic kidney disease (ARPKD), the most common ciliopathy of childhood, is characterized by congenital hepatic fibrosis and progressive cystic degeneration of kidneys. We aimed to describe congenital hepatic fibrosis in patients with ARPKD, confirmed by detection of mutations in PKHD1. METHODS: Patients with ARPKD and congenital hepatic fibrosis were evaluated at the National Institutes of Health from 2003 to 2009. We analyzed clinical, molecular, and imaging data from 73 patients (age, 1-56 years; average, 12.7 ± 13.1 years) with kidney and liver involvement (based on clinical, imaging, or biopsy analyses) and mutations in PKHD1. RESULTS: Initial symptoms were liver related in 26% of patients, and others presented with kidney disease. One patient underwent liver and kidney transplantation, and 10 others received kidney transplants. Four presented with cholangitis and one with variceal bleeding. Sixty-nine percent of patients had enlarged left lobes on magnetic resonance imaging, 92% had increased liver echogenicity on ultrasonography, and 65% had splenomegaly. Splenomegaly started early in life; 60% of children younger than 5 years had enlarged spleens. Spleen volume had an inverse correlation with platelet count and prothrombin time but not with serum albumin level. Platelet count was the best predictor of spleen volume (area under the curve of 0.88905), and spleen length corrected for patient's height correlated inversely with platelet count (R(2) = 0.42, P < .0001). Spleen volume did not correlate with renal function or type of PKHD1 mutation. Twenty-two of 31 patients who underwent endoscopy were found to have varices. Five had variceal bleeding, and 2 had portosystemic shunts. Forty-percent had Caroli syndrome, and 30% had an isolated dilated common bile duct. CONCLUSIONS: Platelet count is the best predictor of the severity of portal hypertension, which has early onset but is underdiagnosed in patients with ARPKD. Seventy percent of patients with ARPKD have biliary abnormalities. Kidney and liver disease are independent, and variability in severity is not explainable by type of PKHD1 mutation; ClinicalTrials.gov number, NCT00068224.


Assuntos
Hipertensão Portal/fisiopatologia , Cirrose Hepática/congênito , Cirrose Hepática/patologia , Rim Policístico Autossômico Recessivo/genética , Receptores de Superfície Celular/genética , Adolescente , Adulto , Fosfatase Alcalina/sangue , Criança , Pré-Escolar , Colangiopancreatografia por Ressonância Magnética , Endoscopia Gastrointestinal , Varizes Esofágicas e Gástricas/etiologia , Feminino , Humanos , Hipertensão Portal/sangue , Hipertensão Portal/complicações , Lactente , Transplante de Rim , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/genética , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Mutação , Tamanho do Órgão , Contagem de Plaquetas , Rim Policístico Autossômico Recessivo/complicações , Pressão na Veia Porta , Tempo de Protrombina , Albumina Sérica , Índice de Gravidade de Doença , Esplenomegalia/diagnóstico por imagem , Ultrassonografia Doppler em Cores , Adulto Jovem , gama-Glutamiltransferase/sangue
15.
Am J Med Genet A ; 152A(10): 2640-5, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20818665

RESUMO

OFD I is an X-linked dominant male-lethal ciliopathy characterized by prominent external features including oral clefts, hamartomas or cysts of the tongue, and digital anomalies. Although these external features are easy to recognize and often lead to diagnosis in early childhood, visceral findings in OFD I, especially the fibrocystic liver and pancreas disease, are under-recognized. In addition, while the occurrence of polycystic kidney disease (PKD) in OFD I is well known, few patients are evaluated and monitored for this complication. We report on two adult females diagnosed with OFD I in infancy, but not evaluated for visceral involvement. In adulthood, they were incidentally found to have severe hypertension and chronic renal insufficiency due to undiagnosed PKD. A pancreatic cystic lesion, also discovered incidentally, was thought to be malignant and led to consideration of major surgery. We present NIH evaluations, including documentation of OFD I mutations, extreme beading of the intrahepatic bile ducts, pancreatic cysts, and tabulate features of reported OFD I cases having hepatic, pancreatic, and renal cystic disease. Liver and pancreas are not routinely evaluated in OFD I patients. Increased awareness and lifelong monitoring of visceral complications, particularly involving the liver, pancreas, and kidney, are essential for timely and accurate treatment.


Assuntos
Fibrose Cística/genética , Cirrose Hepática/genética , Rim Policístico Autossômico Dominante/genética , Proteínas/genética , Anormalidades Múltiplas/genética , Adulto , Fibrose Cística/complicações , Éxons/genética , Feminino , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Deleção de Sequência , Língua/anormalidades
16.
Clin J Am Soc Nephrol ; 5(6): 972-84, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20413436

RESUMO

BACKGROUND AND OBJECTIVES: Renal function and imaging findings have not been comprehensively and prospectively characterized in a broad age range of patients with molecularly confirmed autosomal recessive polycystic kidney disease (ARPKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Ninety potential ARPKD patients were examined at the National Institutes of Health Clinical Center. Seventy-three fulfilled clinical diagnostic criteria, had at least one PKHD1 mutation, and were prospectively evaluated using magnetic resonance imaging (MRI), high-resolution ultrasonography (HR-USG), and measures of glomerular and tubular function. RESULTS: Among 31 perinatally symptomatic patients, 25% required renal replacement therapy by age 11 years; among 42 patients who became symptomatic beyond 1 month (nonperinatal), 25% required kidney transplantation by age 32 years. Creatinine clearance (CrCl) for nonperinatal patients (103 +/- 54 ml/min/1.73 m(2)) was greater than for perinatal patients (62 +/- 33) (P = 0.002). Corticomedullary involvement on HR-USG was associated with a significantly worse mean CrCl (61 +/- 32) in comparison with medullary involvement only (131 +/- 46) (P < 0.0001). Among children with enlarged kidneys, volume correlated inversely with function, although with wide variability. Severity of PKHD1 mutations did not determine kidney size or function. In 35% of patients with medullary-only abnormalities, standard ultrasound was normal and the pathology was detectable with HR-USG. CONCLUSIONS: In ARPKD, perinatal presentation and corticomedullary involvement are associated with faster progression of kidney disease. Mild ARPKD is best detected by HR-USG. Considerable variability occurs that is not explained by the type of PKHD1 mutation.


Assuntos
Genes Recessivos , Rim/patologia , Rim/fisiopatologia , Doenças Renais Policísticas/genética , Receptores de Superfície Celular/genética , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Criança , Pré-Escolar , Creatinina/urina , Cistatina C/sangue , Análise Mutacional de DNA , Progressão da Doença , Feminino , Predisposição Genética para Doença , Taxa de Filtração Glomerular , Humanos , Lactente , Estimativa de Kaplan-Meier , Rim/diagnóstico por imagem , Túbulos Renais/patologia , Túbulos Renais/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Tamanho do Órgão , Linhagem , Fenótipo , Doenças Renais Policísticas/patologia , Doenças Renais Policísticas/fisiopatologia , Doenças Renais Policísticas/terapia , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Ultrassonografia , Estados Unidos , Adulto Jovem
17.
Mol Genet Metab ; 99(2): 160-73, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19914852

RESUMO

PKHD1, the gene mutated in autosomal recessive polycystic kidney disease (ARPKD)/congenital hepatic fibrosis (CHF), is an exceptionally large and complicated gene that consists of 86 exons and has a number of alternatively spliced transcripts. Its longest open reading frame contains 67 exons that encode a 4074 amino acid protein called fibrocystin or polyductin. The phenotypes caused by PKHD1 mutations are similarly complicated, ranging from perinatally-fatal PKD to CHF presenting in adulthood with mild kidney disease. To date, more than 300 mutations have been described throughout PKHD1. Most reported cohorts include a large proportion of perinatal-onset ARPKD patients; mutation detection rates vary between 42% and 87%. Here we report PKHD1 sequencing results on 78 ARPKD/CHF patients from 68 families. Differing from previous investigations, our study required survival beyond 6 months and included many adults with a CHF-predominant phenotype. We identified 77 PKHD1 variants (41 novel) including 19 truncating, 55 missense, 2 splice, and 1 small in-frame deletion. Using computer-based prediction tools (GVGD, PolyPhen, SNAP), we achieved a mutation detection rate of 79%, ranging from 63% in the CHF-predominant group to 82% in the remaining families. Prediction of the pathogenicity of missense variants will remain challenging until a functional assay is available. In the meantime, use of PKHD1 sequencing data for clinical decisions requires caution, especially when only novel or rare missense variants are identified.


Assuntos
Variação Genética , Cirrose Hepática/congênito , Cirrose Hepática/genética , Rim Policístico Autossômico Recessivo/complicações , Rim Policístico Autossômico Recessivo/genética , Receptores de Superfície Celular/genética , Adolescente , Adulto , Sequência de Bases , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Cirrose Hepática/complicações , Masculino
18.
Hum Mutat ; 30(12): 1611-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19862842

RESUMO

Alkaptonuria (AKU) is a rare autosomal recessive metabolic disorder, characterized by accumulation of homogentisic acid, leading to darkened urine, pigmentation of connective tissue (ochronosis), joint and spine arthritis, and destruction of cardiac valves. AKU is due to mutations in the homogentisate dioxygenase gene (HGD) that converts homogentisic acid to maleylacetoacetic acid in the tyrosine catabolic pathway. Here we report a comprehensive mutation analysis of 93 patients enrolled in our study, as well as an extensive update of all previously published HGD mutations associated with AKU. Within our patient cohort, we identified 52 HGD variants, of which 22 were novel. This yields a total of 91 identified HGD variations associated with AKU to date, including 62 missense, 13 splice site, 10 frameshift, 5 nonsense, and 1 no-stop mutation. Most HGD variants reside in exons 3, 6, 8, and 13. We assessed the potential effect of all missense variations on protein function, using five bioinformatic tools specifically designed for interpretation of missense variants (SIFT, POLYPHEN, PANTHER, PMUT, and SNAP). We also analyzed the potential effect of splice-site variants using two different tools (BDGP and NetGene2). This study provides valuable resources for molecular analysis of alkaptonuria and expands our knowledge of the molecular basis of this disease.


Assuntos
Alcaptonúria/enzimologia , Alcaptonúria/genética , Homogentisato 1,2-Dioxigenase/genética , Mutação/genética , Alcaptonúria/diagnóstico por imagem , Alcaptonúria/patologia , Estudos de Coortes , Éxons/genética , Genótipo , Homogentisato 1,2-Dioxigenase/urina , Ácido Homogentísico/urina , Humanos , National Institutes of Health (U.S.) , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Radiografia , Irmãos , Estados Unidos
19.
Hum Genet ; 119(3): 284-94, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16446975

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphadenopathy, elevated numbers of T cells with alphabeta-T cell receptors but neither CD4 nor CD8 co-receptors, and impaired lymphocyte apoptosis in vitro. Defects in the Fas receptor are the most common cause of ALPS (ALPS Ia), but in rare cases other apoptosis proteins have been implicated, including caspase-10 (ALPS II). We investigated the role of variants of caspase-10 in ALPS. Of 32 unrelated probands with ALPS who did not have Fas defects, two were heterozygous for the caspase-10 missense mutation I406L. Like the previously reported ALPS II-associated mutation L285F, I406L impaired apoptosis when transfected alone and dominantly inhibited apoptosis mediated by wild type caspase-10 in a co-transfection assay. Other variants in caspase-10, V410I and Y446C, were found in 3.4 and 1.6% of chromosomes in Caucasians, and in 0.5 and <0.5% of African Americans, respectively. In contrast to L285F and I406L, these variants had no dominant negative effect in co-transfection assays into the H9 lymphocytic cell line. We found healthy individuals homozygous for V410I, challenging the earlier suggestion that homozygosity for V410I alone causes ALPS. Moreover, an association analysis suggested protection from severe disease by caspase-10 V410I in 63 families with ALPS Ia due to dominant Fas mutations (P<0.05). Thus, different genetic variations in caspase-10 can produce contrasting phenotypic effects.


Assuntos
Doenças Autoimunes/etiologia , Caspase 10/genética , Transtornos Linfoproliferativos/etiologia , Caspase 10/metabolismo , Células Cultivadas , Criança , Pré-Escolar , Família , Feminino , Testes Genéticos , Variação Genética , Humanos , Lactente , Células Jurkat , Masculino , Fenótipo , Síndrome , Transfecção
20.
Clin Immunol ; 118(1): 59-65, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16257267

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte apoptosis characterized by non-malignant lymphadenopathy and splenomegaly, expansion of T cells without either CD4 or CD8 surface markers, and increased incidence of autoimmune diseases and lymphoma. Most patients with ALPS have dominant, heterozygous mutations in tumor necrosis factor receptor superfamily member 6 (TNFRSF6), which encodes CD95, also known as Fas, a mediator of apoptosis. Penetrance and range of disease manifestations in ALPS are highly variable, even among family members who share the same dominant TNFRSF6 mutation. To evaluate HLA as a candidate modifier locus, we typed HLA A, B (including subtypes), and DQB alleles in 356 individuals from 63 unrelated families with defined TNFRSF6 mutations associated with ALPS. We also developed a quantitative severity score and performed statistical analysis. Among the healthier, mutation-bearing individuals, transmission of HLA B44 was significantly overrepresented (nominal P<0.0074) as compared to transmission in patients with severe clinical features of ALPS. The B44 allele may exert a protective role in ALPS.


Assuntos
Doenças Autoimunes/genética , Antígenos HLA-B/genética , Antígenos HLA-B/fisiologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Índice de Gravidade de Doença , Receptor fas/genética , Alelos , Doenças Autoimunes/imunologia , Interpretação Estatística de Dados , Frequência do Gene , Antígenos HLA-B/imunologia , Antígeno HLA-B44 , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ , Teste de Histocompatibilidade , Humanos , Mutação , Receptores do Fator de Necrose Tumoral/genética , Síndrome , Receptor fas/metabolismo
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