Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 98
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Eur J Med Genet ; 66(10): 104825, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37659595

RESUMO

Cholesterol is essential in the brain from the earliest stages of embryonic development. Disruption of cholesterol synthesis pathways that leads to cholesterol deficiency underlies a few syndromes, including desmosterolosis and Smith-Lemli-Opitz syndrome. In both syndromes, brain anomalies can occur. The LSS gene encodes lanosterol synthase (LSS), an important enzyme in the cholesterol biosynthesis pathway. Biallelic pathogenic variants in this gene cause alopecia-intellectual disability type 4 syndrome (APMR4, MIM 618840), a rare autosomal recessive disorder. Here, we describe two new LSS variants (c.1016C > T; p. Ser339Leu and c.1522G > C; p. Gly508Arg) found in a compound heterozygous fetus diagnosed prenatally with brain abnormalities by ultrasound scanning. Two of his siblings from the same parents also harbored these variants. Both siblings had alopecia, mild intellectual disability, autism spectrum disorder, and cataracts. To the best of our knowledge, this case represents the first prenatal diagnosis of APMR4 first suspected by ultrasound. In addition, the phenotypic features of the siblings are extensive compared with those described in previous reports and include abnormal corpus callosum, cataracts, alopecia, and developmental delay.


Assuntos
Transtorno do Espectro Autista , Catarata , Deficiência Intelectual , Gravidez , Feminino , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Diagnóstico Pré-Natal , Alopecia/genética , Colesterol/genética , Colesterol/metabolismo
2.
Prenat Diagn ; 42(7): 881-889, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34132406

RESUMO

OBJECTIVE: To explain the importance of identifying an etiology for the pathological finding of nonimmune hydrops fetalis (NIHF) and to explore the impact of exome sequencing in recurrent NIHF. In addition, we present two cases of pregnancies affected with recurrent NIHF, in which genetic investigation was advantageous. METHODS: Our study aimed to investigate the genetic background, if available, of all fetuses with NIHF referred to our tertiary medical center from January 2013 to August 2020. We summarized the etiology of NIHF if known, sonographic findings, genetic investigation and the pregnancies' outcomes. RESULTS: We encountered 144 families with NIHF. Genetic investigation was performed by chromosomal microarray analysis (CMA) in 63 (63/144. 44%) fetuses. Seventeen of 63 (27%) had a positive CMA result. In the negative CMA group, 15 (15/46, 33%) opted for exome sequencing, of which seven exomes were positive (47%). Among these, there were four couples with recurrent pregnancies affected by hydrops. Among the remaining 11 exome investigations for non-recurrent hydrops, another three were diagnostic. CONCLUSION: As identifying the etiology of the NIHF is an invaluable tool for the prognosis of the pregnancy, exome sequencing can provide further elucidation of the underlying pathogenesis of NIHF. Thus, genetic investigation should be recommended for cases of NIHF.


Assuntos
Exoma , Hidropisia Fetal , Feminino , Feto , Humanos , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/genética , Gravidez , Resultado da Gravidez , Sequenciamento do Exoma
3.
J Clin Endocrinol Metab ; 107(5): 1346-1356, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-34971397

RESUMO

CONTEXT: The hyperinsulinism/hyperammonemia (HI/HA) syndrome, the second-most common form of congenital hyperinsulinism, has been associated with dominant mutations in GLUD1, coding for the mitochondrial enzyme glutamate dehydrogenase, that increase enzyme activity by reducing its sensitivity to allosteric inhibition by GTP. OBJECTIVE: To identify the underlying genetic etiology in 2 siblings who presented with the biochemical features of HI/HA syndrome but did not carry pathogenic variants in GLUD1, and to determine the functional impact of the newly identified mutation. METHODS: The patients were investigated by whole exome sequencing. Yeast complementation studies and biochemical assays on the recombinant mutated protein were performed. The consequences of stable slc25a36 silencing in HeLa cells were also investigated. RESULTS: A homozygous splice site variant was identified in solute carrier family 25, member 36 (SLC25A36), encoding the pyrimidine nucleotide carrier 2 (PNC2), a mitochondrial nucleotide carrier that transports pyrimidine as well as guanine nucleotides across the inner mitochondrial membrane. The mutation leads to a 26-aa in-frame deletion in the first repeat domain of the protein, which abolishes transport activity. Furthermore, knockdown of slc25a36 expression in HeLa cells caused a marked reduction in the mitochondrial GTP content, which likely leads to a hyperactivation of glutamate dehydrogenase in our patients. CONCLUSION: We report for the first time a mutation in PNC2/SLC25A36 leading to HI/HA and provide functional evidence of the molecular mechanism responsible for this phenotype. Our findings underscore the importance of mitochondrial nucleotide metabolism and expand the role of mitochondrial transporters in insulin secretion.


Assuntos
Hiperinsulinismo Congênito , Hiperamonemia , Hiperinsulinismo , Hiperinsulinismo Congênito/genética , Glutamato Desidrogenase/genética , Guanosina Trifosfato/metabolismo , Células HeLa , Humanos , Hiperamonemia/genética , Hiperinsulinismo/genética , Hipoglicemia , Mutação , Nucleotídeos
4.
Metab Brain Dis ; 36(4): 581-588, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33471299

RESUMO

Isolated defects in the mitochondrial respiratory chain complex II (CII; succinate-ubiquinone oxidoreductase) are extremely rare and mainly result from bi-allelic mutations in one of the nuclear encoded subunits: SDHA, SDHB and SDHD, which comprise CII and the assembly CII factor SDHAF1. We report an adolescent female who presented with global developmental delay, intellectual disability and childhood onset progressive bilateral optic atrophy. Whole exome sequencing of the patient and her unaffected parents identified the novel heterozygous de novo variant c.1984C > T [NM_004168.4] in the SDHA gene. Biochemical assessment of CII in the patient's derived fibroblasts and lymphocytes displayed considerably decreased CII residual activity compared with normal controls, when normalized to the integral mitochondrial enzyme citrate synthase. Protein modeling of the consequent p.Arg662Cys variant [NP-004159.2] suggested that this substitution will compromise the structural integrity of the FAD-binding protein at the C-terminus that will ultimately impair the FAD binding to SDHA, thus decreasing the entire CII activity. Our study emphasizes the role of certain heterozygous SDHA mutations in a distinct clinical phenotype dominated by optic atrophy and neurological impairment. This is the second mutation that has been reported to cause this phenotype. Furthermore, it adds developmental delay and cognitive disability to the expanding spectrum of the disorder. We propose to add SDHA to next generation sequencing gene panels of optic atrophy.


Assuntos
Disfunção Cognitiva/genética , Complexo II de Transporte de Elétrons/genética , Variação Genética/genética , Heterozigoto , Atrofia Óptica/genética , Adolescente , Sequência de Aminoácidos , Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico por imagem , Complexo II de Transporte de Elétrons/química , Feminino , Humanos , Atrofia Óptica/complicações , Atrofia Óptica/diagnóstico por imagem , Estrutura Secundária de Proteína
5.
J Inherit Metab Dis ; 44(3): 606-617, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33190319

RESUMO

Urea cycle disorders (UCDs), including OTC deficiency (OTCD), are life-threatening diseases with a broad clinical spectrum. Early diagnosis and initiation of treatment based on a newborn screening (NBS) test for OTCD with high specificity and sensitivity may contribute to reduction of the significant complications and high mortality. The efficacy of incorporating orotic acid determination into routine NBS was evaluated. Combined measurement of orotic acid and citrulline in archived dried blood spots from newborns with urea cycle disorders and normal controls was used to develop an algorithm for routine NBS for OTCD in Israel. Clinical information and genetic confirmation results were obtained from the follow-up care providers. About 1147986 newborns underwent routine NBS including orotic acid determination, 25 of whom were ultimately diagnosed with a UCD. Of 11 newborns with OTCD, orotate was elevated in seven but normal in two males with early-onset and two males with late-onset disease. Orotate was also elevated in archived dried blood spots of all seven retrospectively tested historical OTCD patients, only three of whom had originally been identified by NBS with low citrulline and elevated glutamine. Among the other UCDs emerge, three CPS1D cases and additional three retrospective CPS1D cases otherwise reported as a very rare condition. Combined levels of orotic acid and citrulline in routine NBS can enhance the detection of UCD, especially increasing the screening sensitivity for OTCD and differentiate it from CPS1D. Our data and the negligible extra cost for orotic acid determination might contribute to the discussion on screening for proximal UCDs in routine NBS.


Assuntos
Citrulina/sangue , Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , Ácido Orótico/sangue , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Teste em Amostras de Sangue Seco , Feminino , Humanos , Recém-Nascido , Israel/epidemiologia , Masculino , Triagem Neonatal , Doença da Deficiência de Ornitina Carbomoiltransferase/epidemiologia , Estudos Retrospectivos , Distúrbios Congênitos do Ciclo da Ureia/epidemiologia
6.
J Clin Immunol ; 41(1): 147-162, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33111199

RESUMO

PURPOSE: Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine with the potential of causing severe iatrogenic complications in patients with primary immunodeficiency diseases (PID) before and after hematopoietic stem cell transplantation (HSCT). We aim to investigate risk factors of post-HSCT BCG-related complications in PID patients. METHODS: A retrospective analysis of pediatric PID patients who had received the BCG vaccine and underwent HSCT at Hadassah-Hebrew University Medical Center, between 2007 and 2019. RESULTS: We found 15/36 (41.67%) patients who developed post-HSCT BCG-related complications. The most significant risk factor for developing BCG-related complications was T cell deficiency (47.6% of the non-complicated vs 83.3% of the BCGitis and 100% of the BCGosis groups had T cell lymphopenia, p = 0.013). None of the chronic granulomatous patients developed BCG-related manifestation post-transplant. Among T cell-deficient patients, lower NK (127 vs 698 cells/µl, p = 0.04) cell counts and NK-SCID were risk factors for ongoing post-HSCT BCGosis, as was pretransplant disseminated BCGosis (33.3% of patients with BCGosis vs none of the non-BCGosis patients, p = 0.04). Immune reconstitution inflammatory syndrome (IRIS) was observed in 3/5 patients with Omenn syndrome. Prophylactic antimycobacterial treatment was not proven effective. CONCLUSION: BCG vaccination can cause significant morbidity and mortality in the post-transplant T cell-deficient patient, especially in the presence of pre-transplant disease. Taking a detailed medical history prior to administering, the BCG vaccine is crucial for prevention of this complication.


Assuntos
Vacina BCG/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hospedeiro Imunocomprometido , Doenças da Imunodeficiência Primária/complicações , Doenças da Imunodeficiência Primária/imunologia , Vacina BCG/imunologia , Biomarcadores , Pré-Escolar , Diagnóstico Diferencial , Suscetibilidade a Doenças , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Avaliação de Resultados da Assistência ao Paciente , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/terapia , Estudos Retrospectivos , Vacinação/efeitos adversos
7.
Nat Commun ; 11(1): 5518, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139704

RESUMO

Full genome sequences are increasingly used to track the geographic spread and transmission dynamics of viral pathogens. Here, with a focus on Israel, we sequence 212 SARS-CoV-2 sequences and use them to perform a comprehensive analysis to trace the origins and spread of the virus. We find that travelers returning from the United States of America significantly contributed to viral spread in Israel, more than their proportion in incoming infected travelers. Using phylodynamic analysis, we estimate that the basic reproduction number of the virus was initially around 2.5, dropping by more than two-thirds following the implementation of social distancing measures. We further report high levels of transmission heterogeneity in SARS-CoV-2 spread, with between 2-10% of infected individuals resulting in 80% of secondary infections. Overall, our findings demonstrate the effectiveness of social distancing measures for reducing viral spread.


Assuntos
Betacoronavirus/genética , Doenças Transmissíveis Importadas/virologia , Infecções por Coronavirus/transmissão , Genoma Viral/genética , Pneumonia Viral/transmissão , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Número Básico de Reprodução/estatística & dados numéricos , COVID-19 , Criança , Pré-Escolar , Doenças Transmissíveis Importadas/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Feminino , Humanos , Lactente , Recém-Nascido , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Pandemias/prevenção & controle , Filogenia , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Distância Psicológica , RNA Viral/genética , SARS-CoV-2 , Análise de Sequência de RNA , Estados Unidos , Adulto Jovem
8.
Proc Natl Acad Sci U S A ; 117(36): 22113-22121, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32843346

RESUMO

RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.


Assuntos
Citomegalovirus/fisiologia , Fibroblastos/imunologia , Fibroblastos/virologia , RNA Polimerase III/metabolismo , Animais , Chlorocebus aethiops , Citomegalovirus/imunologia , Células Dendríticas , Regulação Enzimológica da Expressão Gênica , Humanos , Mutação , RNA Polimerase III/genética , Células Vero
9.
Eur J Med Genet ; 63(6): 103901, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32151765

RESUMO

BACKGROUND: Maple syrup urine disease is a rare autosomal-recessive aminoacidopathy, caused by deficient branched-chain 2-keto acid dehydrogenase (BCKD), with subsequent accumulation of branched-chain amino acids (BCAAs): leucine, isoleucine and valine. While most cases of MSUD are classic, some 20% of cases are non-classic variants, designated as intermediate- or intermittent-types. Patients with the latter form usually develop normally and are cognitively intact, with normal BCAA levels when asymptomatic. However, intercurrent febrile illness and catabolism may cause metabolic derailment with life-threatening neurological sequelae. Thus, early detection and dietary intervention are warranted in intermittent MSUD. PATIENTS AND METHODS: We describe eight patients from four unrelated families, diagnosed with intermittent MSUD. Their presenting symptoms during metabolic crises varied from confusion and decreased consciousness, to ataxia, and acute psychosis. Molecular confirmation of MSUD was pursued via sequencing of the BCKDHA, BCKDHB and DBT genes. RESULTS: All affected individuals were found to harbor bi-allelic pathogenic variants in either BCKDHB or DBT. Of the seven variants, four variants in BCKDHB (p.G101D, p. V103A, p. A221D, p. Y195C) and one variant in DBT (p.K427E) were not previously described. CONCLUSIONS: While newborn screening programs allow for early detection of classic MSUD, cases of the intermittent form might go undetected, and present later in childhood following metabolic derailment, with an array of non-specific symptoms. Our experience with the families reported herein adds to the current knowledge regarding the phenotype and mutational spectrum of this unique inborn error of branched-chain amino acid metabolism, and underscore the high index of suspicion required for its diagnosis.


Assuntos
Testes Genéticos/métodos , Doença da Urina de Xarope de Bordo/diagnóstico , Mutação , Fenótipo , Adolescente , Criança , Pré-Escolar , Progressão da Doença , Feminino , Testes Genéticos/normas , Humanos , Masculino , Doença da Urina de Xarope de Bordo/genética , Proteínas Quinases/genética
10.
Am J Med Genet A ; 182(4): 689-696, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32027463

RESUMO

Trio exome sequencing is a powerful tool in the molecular investigation of monogenic disorders and provides an incremental diagnostic yield over proband-only sequencing, mainly due to the rapid identification of de novo disease-causing variants. However, heterozygous variants inherited from unaffected parents may be inadvertently dismissed, although multiple explanations are available for such scenarios including mosaicism in the parent, incomplete penetrance, imprinting, or skewed X-inactivation. We report three probands, in which a pathogenic or likely pathogenic variant was identified upon exome sequencing, yet was inherited from an unaffected parent. Segregation of the variants (in NOTCH1, PHF6, and SOX10) in the grandparent generation revealed that the variant was de novo in each case. Additionally, one proband had skewed X-inactivation. We discuss the possible genetic mechanism in each case, and urge caution in data interpretation of exome sequencing data. We illustrate the utility of expanding segregation studies to the grandparent generation and demonstrate the impact on exome interpretation strategies, by showing that objective genotype data can overcome subjective parental report of lack of symptoms.


Assuntos
Epilepsia/genética , Exoma/genética , Predisposição Genética para Doença , Avós , Síndrome do Coração Esquerdo Hipoplásico/genética , Mutação , Adulto , Criança , Epilepsia/patologia , Feminino , Testes Genéticos , Genótipo , Humanos , Síndrome do Coração Esquerdo Hipoplásico/patologia , Recém-Nascido , Masculino , Mosaicismo , Pais , Receptor Notch1/genética , Proteínas Repressoras/genética , Fatores de Transcrição SOXE/genética , Sequenciamento do Exoma
11.
Am J Hum Genet ; 105(1): 48-64, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31178128

RESUMO

We report biallelic missense and frameshift pathogenic variants in the gene encoding human nucleoporin NUP214 causing acute febrile encephalopathy. Clinical symptoms include neurodevelopmental regression, seizures, myoclonic jerks, progressive microcephaly, and cerebellar atrophy. NUP214 and NUP88 protein levels were reduced in primary skin fibroblasts derived from affected individuals, while the total number and density of nuclear pore complexes remained normal. Nuclear transport assays exhibited defects in the classical protein import and mRNA export pathways in affected cells. Direct surface imaging of fibroblast nuclei by scanning electron microscopy revealed a large increase in the presence of central particles (known as "plugs") in the nuclear pore channels of affected cells. This observation suggests that large transport cargoes may be delayed in passage through the nuclear pore channel, affecting its selective barrier function. Exposure of fibroblasts from affected individuals to heat shock resulted in a marked delay in their stress response, followed by a surge in apoptotic cell death. This suggests a mechanistic link between decreased cell survival in cell culture and severe fever-induced brain damage in affected individuals. Our study provides evidence by direct imaging at the single nuclear pore level of functional changes linked to a human disease.


Assuntos
Encefalopatia Aguda Febril/etiologia , Fibroblastos/patologia , Mutação da Fase de Leitura , Canais Iônicos/fisiologia , Mutação de Sentido Incorreto , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Poro Nuclear/patologia , Transporte Ativo do Núcleo Celular , Encefalopatia Aguda Febril/metabolismo , Encefalopatia Aguda Febril/patologia , Apoptose , Núcleo Celular/genética , Núcleo Celular/metabolismo , Proliferação de Células , Células Cultivadas , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Humanos , Lactente , Masculino , Poro Nuclear/genética , Poro Nuclear/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/química , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Linhagem , Conformação Proteica
12.
Nat Commun ; 10(1): 605, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30723199

RESUMO

Nuclear envelopathies comprise a heterogeneous group of diseases caused by mutations in genes encoding nuclear envelope proteins. Mutations affecting lamina-associated polypeptide 1 (LAP1) result in two discrete phenotypes of muscular dystrophy and progressive dystonia with cerebellar atrophy. We report 7 patients presenting at birth with severe progressive neurological impairment, bilateral cataract, growth retardation and early lethality. All the patients are homozygous for a nonsense mutation in the TOR1AIP1 gene resulting in the loss of both protein isoforms LAP1B and LAP1C. Patient-derived fibroblasts exhibit changes in nuclear envelope morphology and large nuclear-spanning channels containing trapped cytoplasmic organelles. Decreased and inefficient cellular motility is also observed in these fibroblasts. Our study describes the complete absence of both major human LAP1 isoforms, underscoring their crucial role in early development and organogenesis. LAP1-associated defects may thus comprise a broad clinical spectrum depending on the availability of both isoforms in the nuclear envelope throughout life.


Assuntos
Anormalidades Múltiplas/genética , Predisposição Genética para Doença/genética , Proteínas de Membrana/genética , Mutação , Membrana Nuclear/genética , Proteínas Nucleares/genética , Anormalidades Múltiplas/metabolismo , Sequência de Bases , Criança , Pré-Escolar , Proteínas do Citoesqueleto , Análise Mutacional de DNA , Evolução Fatal , Feminino , Humanos , Masculino , Proteínas de Membrana/metabolismo , Microscopia Eletrônica de Transmissão , Membrana Nuclear/metabolismo , Membrana Nuclear/ultraestrutura , Proteínas Nucleares/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
13.
Metab Brain Dis ; 34(2): 557-563, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30637540

RESUMO

D-glycerate 2 kinase (DGK) is an enzyme that mediates the conversion of D-glycerate, an intermediate metabolite of serine and fructose metabolism, to 2-phosphoglycerate. Deficiency of DGK leads to accumulation of D-glycerate in various tissues and its massive excretion in urine. D-glyceric aciduria (DGA) is an autosomal recessive metabolic disorder caused by mutations in the GLYCTK gene. The clinical spectrum of DGA is highly variable, ranging from severe progressive infantile encephalopathy to a practically asymptomatic condition. We describe a male patient from a consanguineous Arab family with infantile onset of DGA, characterized by profound psychomotor retardation, progressive microcephaly, intractable seizures, cortical blindness and deafness. Consecutive brain MR imaging showed an evolving brain atrophy, thinning of the corpus callosum and diffuse abnormal white matter signals. Whole exome sequencing identified the homozygous missense variant in the GLYCTK gene [c.455 T > C, NM_145262.3], which affected a highly conserved leucine residue located at a domain of yet unknown function of the enzyme [p.Leu152Pro, NP_660305]. In silico analysis of the variant supported its pathogenicity. A review of the 15 previously reported patients, together with the current one, confirms a clear association between DGA and severe neurological impairment. Yet, future studies of additional patients with DGA are required to better understand the clinical phenotype and pathogenesis.


Assuntos
Encefalopatias/metabolismo , Epilepsia/metabolismo , Hiperoxalúria Primária/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Encefalopatias/genética , Criança , Epilepsia/diagnóstico , Epilepsia/genética , Ácidos Glicéricos/metabolismo , Humanos , Hiperoxalúria Primária/genética , Lactente , Masculino , Mutação/genética , Fenótipo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Espasmos Infantis/genética , Espasmos Infantis/metabolismo
14.
Am J Hum Genet ; 104(1): 179-185, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595371

RESUMO

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) initiates a stress response mechanism to clear out the unfolded proteins by either facilitating their re-folding or inducing their degradation. When this fails, an apoptotic cascade is initiated so that the affected cell is eliminated. IRE1α is a critical sensor of the unfolded-protein response, essential for initiating the apoptotic signaling. Here, we report an infantile neurodegenerative disorder associated with enhanced activation of IRE1α and increased apoptosis. Three unrelated affected individuals with congenital microcephaly, infantile epileptic encephalopathy, and profound developmental delay were found to carry heterozygous variants (c.932T>C [p.Leu311Ser] or c.935T>C [p.Leu312Pro]) in RNF13, which codes for an IRE1α-interacting protein. Structural modeling predicted that the variants, located on the surface of the protein, would not alter overall protein folding. Accordingly, the abundance of RNF13 and IRE1α was not altered in affected individuals' cells. However, both IRE1α-mediated stress signaling and stress-induced apoptosis were increased in affected individuals' cells. These results indicate that the RNF13 variants confer gain of function to the encoded protein and thereby lead to altered signaling of the ER stress response associated with severe neurodegeneration in infancy.


Assuntos
Cegueira/congênito , Cegueira/genética , Insuficiência de Crescimento/genética , Mutação com Ganho de Função , Heterozigoto , Microcefalia/genética , Espasmos Infantis/genética , Ubiquitina-Proteína Ligases/genética , Sequência de Aminoácidos , Apoptose , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Estresse do Retículo Endoplasmático , Humanos , Lactente , Masculino , Modelos Moleculares , Espasmos Infantis/congênito , Ubiquitina-Proteína Ligases/química , Resposta a Proteínas não Dobradas
15.
PLoS Genet ; 14(8): e1007602, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30148830

RESUMO

The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly.


Assuntos
Códon sem Sentido , Lateralidade Funcional/genética , Homozigoto , Infertilidade Masculina/genética , Proteínas Nucleares/metabolismo , Adolescente , Adulto , Animais , Dineínas do Axonema/genética , Dineínas do Axonema/metabolismo , Axonema/metabolismo , Proteínas de Ciclo Celular , Criança , Pré-Escolar , Cílios/ultraestrutura , Feminino , Regulação da Expressão Gênica , Ligação Genética , Humanos , Lactente , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Cauda do Espermatozoide , Sequenciamento do Exoma , Adulto Jovem
16.
Neurogenetics ; 19(4): 227-235, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30043326

RESUMO

The major facilitator superfamily domain-containing protein 2A (MFSD2A) is a constituent of the blood-brain barrier and functions to transport lysophosphatidylcholines (LPCs) into the central nervous system. LPCs such as that derived from docosahexanoic acid (DHA) are indispensable to neurogenesis and maintenance of neurons, yet cannot be synthesized within the brain and are dependent on MFSD2A for brain uptake. Recent studies have implicated MFSD2A mutations in lethal and non-lethal microcephaly syndromes, with the severity correlating to the residual activity of the transporter. We describe two siblings with shared parental ancestry, in whom we identified a homozygous missense mutation (c.1205C > A; p.Pro402His) in MFSD2A. Both affected individuals had microcephaly, hypotonia, appendicular spasticity, dystonia, strabismus, and global developmental delay. Neuroimaging revealed paucity of white matter with enlarged lateral ventricles. Plasma lysophosphatidylcholine (LPC) levels were elevated, reflecting reduced brain transport. Cell-based studies of the p.Pro402His mutant protein indicated complete loss of activity of the transporter despite the non-lethal, attenuated phenotype. The aggregate data of MFSD2A-associated genotypes and phenotypes suggest that additional factors, such as nutritional supplementation or modifying genetic factors, may modulate the severity of disease and call for consideration of treatment options for affected individuals.


Assuntos
Doenças Desmielinizantes/genética , Ácidos Docosa-Hexaenoicos/metabolismo , Microcefalia/genética , Mutação de Sentido Incorreto , Proteínas Supressoras de Tumor/genética , Substituição de Aminoácidos , Animais , Transporte Biológico/genética , Barreira Hematoencefálica/metabolismo , Criança , Pré-Escolar , Doenças Desmielinizantes/metabolismo , Deficiências do Desenvolvimento/genética , Feminino , Células HEK293 , Homozigoto , Humanos , Metabolismo dos Lipídeos/genética , Lisofosfatidilcolinas/metabolismo , Masculino , Camundongos , Camundongos Knockout , Microcefalia/metabolismo , Modelos Moleculares , Bainha de Mielina/metabolismo , Linhagem , Irmãos , Simportadores , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/metabolismo
17.
Eur J Med Genet ; 61(10): 616-620, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29655802

RESUMO

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNA with cognate amino acids during protein translation. Non-canonical functions are increasingly recognized, and include transcription and translation control and extracellular signaling. Monoallelic mutations in genes encoding several ARSs have been identified in axonal Charcot-Marie-Tooth (CMT2) disease, whereas biallelic mutations in ARS loci have been associated with multi-tissue syndromes, variably involving the central nervous system, lung, and liver. We report a male infant of non-consanguineous origin, presenting with successive onset of transfusion-dependent anemia, hypothyroidism, cholestasis, interstitial lung disease, and developmental delay. Whole-exome sequencing (WES) revealed compound heterozygosity for two variants (p.Tyr307Cys and p.Arg618Cys) in MARS, encoding methionyl-tRNA synthetase. Biallelic MARS mutations are associated with interstitial lung and liver disease (ILLD). Interestingly, the p.Arg618Cys variant, inherited from an unaffected father, was previously reported in a family with autosomal dominant late-onset CMT2. Yeast complementation assays confirmed pathogenicity of p.Arg618Cys, yet suggested retained function of p.Tyr307Cys. Our findings underscore the phenotypic variability associated with ARS mutations, and suggest genetic or environmental modifying factors in the onset of monoallelic MARS-associated CMT2.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Colestase/genética , Deficiências do Desenvolvimento/genética , Doenças Pulmonares Intersticiais/genética , Metionina tRNA Ligase/genética , Mutação de Sentido Incorreto , Fenótipo , Colestase/diagnóstico , Deficiências do Desenvolvimento/patologia , Genes Dominantes , Genes Recessivos , Humanos , Lactente , Doenças Pulmonares Intersticiais/diagnóstico , Masculino , Linhagem , Saccharomyces cerevisiae/genética , Síndrome
18.
Am J Med Genet A ; 176(1): 92-98, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29130579

RESUMO

The primary cilium is a key organelle in numerous physiological and developmental processes. Genetic defects in the formation of this non-motile structure, in its maintenance and function, underlie a wide array of ciliopathies in human, including craniofacial, brain and heart malformations, and retinal and hearing defects. We used exome sequencing to study the molecular basis of disease in an 11-year-old female patient who suffered from growth retardation, global developmental delay with absent speech acquisition, agenesis of corpus callosum and paucity of white matter, sensorineural deafness, retinitis pigmentosa, vertebral anomalies, patent ductus arteriosus, and facial dysmorphism reminiscent of STAR syndrome, a suspected ciliopathy. A homozygous variant, c.870_871del, was identified in the CDK10 gene, predicted to cause a frameshift, p.Trp291Alafs*18, in the cyclin-dependent kinase 10 protein. CDK10 mRNAs were detected in patient cells and do not seem to undergo non-sense mediated decay. CDK10 is the binding partner of Cyclin M (CycM) and CDK10/CycM protein kinase regulates ciliogenesis and primary cilium elongation. Notably, CycM gene is mutated in patients with STAR syndrome. Following incubation, the patient cells appeared less elongated and more densely populated than the control cells suggesting that the CDK10 mutation affects the cytoskeleton. Upon starvation and staining with acetylated-tubulin, γ-tubulin, and Arl13b, the patient cells exhibited fewer and shorter cilia than control cells. These findings underscore the importance of CDK10 for the regulation of ciliogenesis. CDK10 defect is likely associated with a new form of ciliopathy phenotype; additional patients may further validate this association.


Assuntos
Agenesia do Corpo Caloso/genética , Quinases Ciclina-Dependentes , Surdez/genética , Estudos de Associação Genética , Homozigoto , Mutação , Displasia Retiniana/genética , Agenesia do Corpo Caloso/diagnóstico , Alelos , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Criança , Análise Mutacional de DNA , Surdez/diagnóstico , Exoma , Fácies , Feminino , Expressão Gênica , Humanos , Linhagem , Fenótipo , RNA Mensageiro/genética , Displasia Retiniana/diagnóstico
19.
Am J Hum Genet ; 101(2): 267-273, 2017 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-28777933

RESUMO

Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5'- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.


Assuntos
Encefalopatias/genética , Nucléolo Celular/patologia , Doenças Neurodegenerativas/genética , Proteínas Pol1 do Complexo de Iniciação de Transcrição/genética , RNA Ribossômico 18S/biossíntese , Adolescente , Adulto , Atrofia/genética , Encéfalo/patologia , Encefalopatias/patologia , Criança , Cromatina/metabolismo , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Doenças Neurodegenerativas/patologia , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Adulto Jovem
20.
Am J Hum Genet ; 101(2): 291-299, 2017 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-28777934

RESUMO

Progressive childhood encephalopathy is an etiologically heterogeneous condition characterized by progressive central nervous system dysfunction in association with a broad range of morbidity and mortality. The causes of encephalopathy can be either non-genetic or genetic. Identifying the genetic causes and dissecting the underlying mechanisms are critical to understanding brain development and improving treatments. Here, we report that variants in TRAPPC12 result in progressive childhood encephalopathy. Three individuals from two unrelated families have either a homozygous deleterious variant (c.145delG [p.Glu49Argfs∗14]) or compound-heterozygous variants (c.360dupC [p.Glu121Argfs∗7] and c.1880C>T [p. Ala627Val]). The clinical phenotypes of the three individuals are strikingly similar: severe disability, microcephaly, hearing loss, spasticity, and characteristic brain imaging findings. Fibroblasts derived from all three individuals showed a fragmented Golgi that could be rescued by expression of wild-type TRAPPC12. Protein transport from the endoplasmic reticulum to and through the Golgi was delayed. TRAPPC12 is a member of the TRAPP protein complex, which functions in membrane trafficking. Variants in several other genes encoding members of the TRAPP complex have been associated with overlapping clinical presentations, indicating shared and distinct functions for each complex member. Detailed understanding of the TRAPP-opathies will illuminate the role of membrane protein transport in human disease.


Assuntos
Encefalopatias/genética , Retículo Endoplasmático/metabolismo , Complexo de Golgi/patologia , Proteínas de Membrana Transportadoras/genética , Transporte Proteico/genética , Fatores de Transcrição/genética , Atrofia/patologia , Sequência de Bases , Encéfalo/patologia , Encefalopatias/patologia , Células Cultivadas , Pré-Escolar , Exoma/genética , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Transporte Proteico/fisiologia , Análise de Sequência de DNA
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...