RESUMEN
SGPL1 encodes sphingosine-1-phosphate lyase, the final enzyme of sphingolipid metabolism. In 2017, a condition featuring steroid-resistant nephrotic syndrome and/or adrenal insufficiency associated with pathogenic SGPL1 variants was reported. In addition to the main features of the disease, patients often exhibit a range of neurologic deficits. In a handful of cases, brain imaging results were described. However, high-quality imaging results and a systematic analysis of brain MR imaging findings associated with the condition are lacking. In this study, MR images from 4 new patients and additional published case reports were reviewed by a pediatric neuroradiologist. Analysis reveals recurring patterns of features in affected patients, including isolated callosal dysgenesis and prominent involvement of the globus pallidus, thalamus, and dentate nucleus, with progressive atrophy and worsening of brain lesions. MR imaging findings of abnormal deep gray nuclei, microcephaly, or callosal dysgenesis in an infant or young child exhibiting other typical clinical features of sphingosine-1-phosphate lyase insufficiency syndrome should trigger prompt genetic testing for SGPL1 mutations.
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Aldehído-Liasas/deficiencia , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Errores Innatos del Metabolismo/diagnóstico por imagen , Errores Innatos del Metabolismo/patología , Aldehído-Liasas/genética , Niño , Preescolar , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Errores Innatos del Metabolismo/genética , Mutación , Síndrome Nefrótico/enzimología , Síndrome Nefrótico/genética , Síndrome Nefrótico/patologíaRESUMEN
Autosomal recessive retinitis pigmentosa (arRP) is a clinically and genetically heterogeneous retinal disease that causes blindness. Our purpose was to identify the causal gene, describe the phenotype and delineate the mutation spectrum in a consanguineous Quebec arRP family. We performed Arrayed Primer Extension (APEX) technology to exclude â¼500 arRP mutations in â¼20 genes. Homozygosity mapping [single nucleotide polymorphism (SNP) genotyping] identified 10 novel significant homozygous regions. We performed next generation sequencing and whole exome capture. Sanger sequencing provided cosegregation. We screened another 150 retinitis pigmentosa (RP) and 200 patients with Senior-Løken Syndrome (SLS). We identified a novel missense mutation in WDR19, c.2129T>C which lead to a p.Leu710Ser. We found the same mutation in a second Quebec arRP family. Interestingly, two of seven affected members of the original family developed 'sub-clinical' renal cysts. We hypothesized that more severe WDR19 mutations may lead to severe ciliopathies and found seven WDR19 mutations in five SLS families. We identified a new gene for both arRP and SLS. WDR19 is a ciliary protein associated with the intraflagellar transport machinery. We are currently investigating the full extent of the mutation spectrum. Our findings are crucial in expanding the understanding of childhood blindness and identifying new genes.
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Genes Recesivos , Enfermedades Renales Quísticas/genética , Amaurosis Congénita de Leber/genética , Mutación , Atrofias Ópticas Hereditarias/genética , Proteínas/genética , Retinitis Pigmentosa/genética , Adolescente , Adulto , Niño , Preescolar , Ciliopatías , Consanguinidad , Proteínas del Citoesqueleto , Exoma , Femenino , Estudios de Asociación Genética , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular , Masculino , Linaje , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND/AIMS: Nephrogenic diabetes insipidus (NDI) is a serious condition with large water losses in the urine and the risk of hypernatremic dehydration. Unrecognized, repeated episodes of hypernatremic dehydration can lead to permanent brain damage. Primary NDI is due to mutations in either AVPR2 or AQP2. NDI can also occur as a secondary complication, most commonly from obstructive uropathy or chronic lithium therapy. We observed NDI in patients with inherited tubulopathies and aimed to define the clinical and molecular phenotype. METHODS: We reviewed the medical notes of 4 patients with clinical NDI and an underlying molecularly confirmed diagnosis of nephropathic cystinosis, Bartter syndrome, nephronophthisis and apparent mineralocorticoid excess, respectively. RESULTS: The patients all failed to concentrate their urine after administration of 1-desamino[8-D-arginine] vasopressin. None had an identifiable mutation in AVPR2 or AQP2, consistent with secondary NDI. Patients experienced repeated episodes of hypernatremic dehydration, and in 2 cases, NDI was initially thought to be the primary diagnosis, delaying recognition of the underlying problem. CONCLUSION: The recognition of this potential complication is important as it has direct implications for clinical management. The occurrence of NDI in association with these conditions provides clues for the etiology of aquaporin deficiency.
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Síndrome de Bartter/diagnóstico , Cistinosis/diagnóstico , Diabetes Insípida Nefrogénica/diagnóstico , Enfermedades Renales Quísticas/diagnóstico , Síndrome de Exceso Aparente de Mineralocorticoides/diagnóstico , Síndrome de Bartter/complicaciones , Síndrome de Bartter/genética , Niño , Preescolar , Cistinosis/complicaciones , Cistinosis/genética , Diabetes Insípida Nefrogénica/etiología , Diabetes Insípida Nefrogénica/genética , Femenino , Humanos , Enfermedades Renales Quísticas/complicaciones , Enfermedades Renales Quísticas/congénito , Masculino , Síndrome de Exceso Aparente de Mineralocorticoides/complicaciones , Síndrome de Exceso Aparente de Mineralocorticoides/genética , Mutación/genéticaRESUMEN
Ciliary disorders share typical features, such as polydactyly, renal and biliary cystic dysplasia, and retinitis pigmentosa, which often overlap across diagnostic entities. We report on two siblings of consanguineous parents and two unrelated children, both of unrelated parents, with co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy, an association that adds to the observation of common final patterns of malformations in ciliary disorders. Using homozygosity mapping in the siblings, we were able to exclude all known genes/loci for both syndromes except for INVS, AHI1, and three genes from the previously described Jeune locus at 15q13. No pathogenic variants were found in these genes by direct sequencing. In the third child reported, sequencing of RPGRIP1L, ARL13B, AHI1, TMEM67, OFD1, CC2D2A, and deletion analysis of NPHP1 showed no mutations. Although this study failed to identify a mutation in the patients tested, the co-occurrence of Joubert and Jeune syndromes is likely to represent a distinct entity caused by mutations in a yet to be discovered gene. The mechanisms by which certain organ systems are affected more than others in the spectrum of ciliary diseases remain largely unknown.
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Anomalías Múltiples/genética , Asfixia/genética , Trastornos de la Motilidad Ciliar/genética , Tórax/anomalías , Anomalías Múltiples/diagnóstico , Asfixia/diagnóstico , Niño , Trastornos de la Motilidad Ciliar/diagnóstico , Femenino , Genes , Homocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Radiografía Torácica , Análisis de Secuencia de ADN , SíndromeRESUMEN
BACKGROUND: Bardet-Biedl syndrome (BBS) is primarily an autosomal recessive disorder characterised by the five cardinal features retinitis pigmentosa, postaxial polydactyly, mental retardation, obesity and hypogenitalism. In addition, renal cysts and other anomalies of the kidney and urinary tract can be present. To date, mutations in 12 BBS genes as well as in MKS1 and CEP290 have been identified as causing BBS. The vast genetic heterogeneity of BBS renders molecular genetic diagnosis difficult in terms of the time and cost required to screen all 204 coding exons. METHOD: Here, the use of genome-wide homozygosity mapping as a tool to identify homozygous segments at known BBS loci, in BBS individuals from inbred and outbred background, is reported. RESULTS: In a worldwide cohort of 45 families, causative homozygous mutations in 20 families were identified via direct exon sequencing. Eleven of these mutations were novel, thereby increasing the number of known BBS mutations by 5% (11/218). CONCLUSIONS: Thus, in the presence of extreme genetic locus heterogeneity, homozygosity mapping provides a valuable approach to the molecular genetic diagnosis of BBS and will facilitate the discovery of novel pathogenic mutations.
Asunto(s)
Síndrome de Bardet-Biedl/genética , Mutación , Secuencia de Aminoácidos , Secuencia de Bases , Mapeo Cromosómico/métodos , Estudios de Cohortes , Consanguinidad , Estudios de Asociación Genética , Genoma Humano , Homocigoto , Humanos , Datos de Secuencia Molecular , Fenotipo , Proteínas/genéticaRESUMEN
BACKGROUND: Nephronophthisis (NPHP), a rare recessive cystic kidney disease, is the most frequent genetic cause of chronic renal failure in children and young adults. Mutations in nine genes (NPHP1-9) have been identified. NPHP can be associated with retinal degeneration (Senior-Løken syndrome), brainstem and cerebellar anomalies (Joubert syndrome), or liver fibrosis. METHODS: To identify a causative gene for the subset of patients with associated liver fibrosis, the authors performed a genome wide linkage search in a consanguineous family with three affected patients using 50K SNP microarrays and homozygosity mapping. RESULTS: The authors obtained a significant maximum parametric LOD (logarithm of odds) score of Z(max) = 3.72 on chromosome 8q22 and identified a homozygous missense mutation in the gene MKS3/TMEM67. When examining a worldwide cohort of 62 independent patients with NPHP and associated liver fibrosis we identified altogether four novel mutations (p.W290L, p.C615R, p.G821S, and p.G821R) in five of them. Mutations of MKS3/TMEM67, found recently in Meckel-Gruber syndrome (MKS) type 3 and Joubert syndrome (JBTS) type 6, are predominantly truncating mutations. In contrast, the mutations detected here in patients with NPHP and associated liver fibrosis are exclusively missense mutations. This suggests that they may represent hypomorphic alleles, leading to a milder phenotype compared with the more severe MKS or JBTS phenotype. Additionally, mutation analysis for MKS3/TMEM67 in 120 patients with JBTS yielded seven different (four novel) mutations in five patients, four of whom also presented with congenital liver fibrosis. CONCLUSIONS: Hypomorphic MKS3/TMEM67 mutations cause NPHP with liver fibrosis (NPHP11). This is the first report of MKS3 mutations in patients with no vermian agenesis and without neurological signs. Thus NPHP, JBTS, and MKS represent allelic disorders.
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Enfermedades Renales Quísticas/genética , Cirrosis Hepática/genética , Proteínas de la Membrana/genética , Estudios de Cohortes , Consanguinidad , Haplotipos , Homocigoto , Humanos , Enfermedades Renales Quísticas/complicaciones , Cirrosis Hepática/complicaciones , Escala de Lod , Mutación Missense , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
Joubert syndrome (JS) is an autosomal recessive disorder, consisting of mental retardation, cerebellar vermis aplasia, an irregular breathing pattern, and retinal degeneration. Nephronophthisis (NPHP) is found in 17-27% of these patients, which was designated JS type B. Mutations in four separate genes (AHI1, NPHP1, CEP290/NPHP6, and MKS3) are linked to JS. However, missense mutations in a new ciliary gene (RPGRIP1L) were found in type B patients. We analyzed a cohort of 56 patients with JS type B who were negative for mutations in three (AHI1, NPHP1, and CEP290/NPHP6) of the four genes previously linked to the syndrome. The 26 exons encoding RPGRIP1L were analyzed by means of PCR amplification, CEL I endonuclease digestion, and subsequent sequencing. Using this approach, four different mutations in the RPGRIP1L gene in five different families were identified and three were found to be novel mutations. Additionally, we verified that missense mutations are responsible for JS type B and cluster in exon 15 of the RPGRIP1L gene. Our studies confirm that a T615P mutation represents the most common mutation in the RPGRIP1L gene causing disease in about 8-10% of JS type B patients negative for NPHP1, NPHP6, or AHI1 mutations.
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Enfermedades Cerebelosas/genética , Oftalmopatías/genética , Enfermedades Renales Quísticas/genética , Proteínas/genética , Adulto , Niño , Proteínas del Citoesqueleto , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Ligamiento Genético , Humanos , Masculino , Linaje , Mutación Puntual , SíndromeRESUMEN
Autosomal dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulo-in terstitial nephropathy that causes renal salt wasting, hyperuricemia, gout, and end-stage renal failure in the fifth decade of life. This disorder was described to have an age of onset between the age of 20-30 years or even later. Mutations in the Uromodulin (UMOD) gene were published in patients with familial juvenile hyperuricemic nephropathy (FJHN) and MCKD2. Clinical data and blood samples of 16 affected individuals from 11 different kindreds were collected. Mutational analysis of the UMOD gene was performed by exon polymerase chain reaction (PCR) and direct sequencing. We found the heterozygous C744G (Cys248Trp) mutation, which was originally published by our group, in an additional four kindreds from Europe and Turkey. Age of onset ranged from 3 years to 39 years. The phenotype showed a variety of symptoms such as urinary concentration defect, vesicoureteral reflux, urinary tract infections, hyperuricemia, hypertension, proteinuria, and renal hypoplasia. Haplotype analysis showed cosegragation with the phenotype in all eight affected individuals indicating that the C744G mutation may be due to a founder effect. Moreover, we describe a novel T229G (Cys77Gly) mutation in two affecteds of one kindred. Three of the affected individuals were younger than 10 years at the onset of MCKD2/FJHN. Symptoms include recurrent urinary tract infections compatible with the published phenotype of the Umod knockout mouse model. This emphasizes that MCKD2 is not just a disease of the young adult but is also relevant for children.
Asunto(s)
Hiperuricemia/genética , Enfermedades Renales/genética , Mucoproteínas/genética , Mutación Puntual/genética , Riñón Poliquístico Autosómico Dominante/genética , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Cistina , Análisis Mutacional de ADN , Europa (Continente) , Exones/genética , Femenino , Glicina , Haplotipos/genética , Humanos , Hiperuricemia/orina , Enfermedades Renales/orina , Masculino , Persona de Mediana Edad , Mucoproteínas/orina , Linaje , Fenotipo , Riñón Poliquístico Autosómico Dominante/orina , Turquía , UromodulinaRESUMEN
Congenital nephrotic syndrome is clinically and genetically heterogeneous. The majority of cases can be attributed to mutations in the genes NPHS1, NPHS2, and WT1. By homozygosity mapping in a consanguineous family with isolated congenital nephrotic syndrome, we identified a potential candidate region on chromosome 3p. The LAMB2 gene, which was recently reported as mutated in Pierson syndrome (microcoria-congenital nephrosis syndrome; OMIM #609049), was located in the linkage interval. Sequencing of all coding exons of LAMB2 revealed a novel homozygous missense mutation (R246Q) in both affected children. A different mutation at this codon (R246W), which is highly conserved through evolution, has recently been reported as causing Pierson syndrome. Subsequent LAMB2 mutational screening in six additional families with congenital nephrotic syndrome revealed compound heterozygosity for two novel missense mutations in one family with additional nonspecific ocular anomalies. These findings demonstrate that the spectrum of LAMB2-associated disorders is broader than previously anticipated and includes congenital nephrotic syndrome without eye anomalies or with minor ocular changes different from those observed in Pierson syndrome. This phenotypic variability likely reflects specific genotypes. We conclude that mutational analysis in LAMB2 should be considered in congenital nephrotic syndrome, if no mutations are found in NPHS1, NPHS2, or WT1.
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Genes Recesivos , Laminina/genética , Mutación Missense , Síndrome Nefrótico/genética , Síndrome Nefrótico/patología , Preescolar , Cromosomas Humanos Par 3 , Consanguinidad , Exones , Femenino , Marcadores Genéticos , Haplotipos , Humanos , Intrones , Masculino , Repeticiones de Microsatélite , Mapeo Físico de CromosomaAsunto(s)
Síndrome Branquio Oto Renal/genética , Cromosomas Humanos Par 14/genética , Predisposición Genética a la Enfermedad/genética , Síndrome Branquio Oto Renal/patología , Mapeo Cromosómico , ADN/genética , Salud de la Familia , Femenino , Genoma Humano , Haplotipos/genética , Humanos , Escala de Lod , Masculino , Repeticiones de Microsatélite , LinajeRESUMEN
Nephronophthisis (NPH), an autosomal recessive cystic kidney disease, causes progressive renal failure. The gene for adolescent nephronophthisis (NPHP3) has been mapped to chromosome 3q21-->q22. Senior-Løken syndrome (SLS) describes the association of NPH and Leber congenital amaurosis. Recently a locus for Senior-Løken syndrome (SLSN3) has been localized on chromosome 3q21-->q22 containing the whole critical NPHP3 region. Within the critical NPHP3/SLSN3 region we identified the gene KIAA0678 encoding a DnaJ-like protein. KIAA0678 was considered a good functional candidate gene for NPH3 and SLS3, because molecular cha- perones are involved in the etiology of renal and retinal diseases. Analysis of the genomic structure of KIAA0678 identified 25 exons. For mutational analysis all exons and intron-exon boundaries were amplified and directly sequenced. Affected individuals of two NPH3 families and one SLS family with haplotypes indicative for homozygosity by descent for the NPHP3/SLSN3 locus were studied. No mutation in KIAA0678 was detected. We conclude, KIAA0678 most likely is not responsible for NPH and SLS in the patients studied.
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Proteínas de Choque Térmico/genética , Enfermedades Renales Quísticas/genética , Adolescente , Secuencia de Bases , Mapeo Cromosómico , Cromosomas Humanos Par 3 , Cartilla de ADN , Proteínas del Choque Térmico HSP40 , Humanos , Reacción en Cadena de la Polimerasa , SíndromeRESUMEN
Renal salt loss in Bartter's syndrome is caused by impaired transepithelial transport in the loop of Henle. Sodium chloride is taken up apically by the combined activity of NKCC2 (Na+-K--2Cl- cotransporters) and ROMK potassium channels. Chloride ions exit from the cell through basolateral ClC-Kb chloride channels. Mutations in the three corresponding genes have been identified that correspond to Bartter's syndrome types 1-3. The gene encoding the integral membrane protein barttin is mutated in a form of Bartter's syndrome that is associated with congenital deafness and renal failure. Here we show that barttin acts as an essential beta-subunit for ClC-Ka and ClC-Kb chloride channels, with which it colocalizes in basolateral membranes of renal tubules and of potassium-secreting epithelia of the inner ear. Disease-causing mutations in either ClC-Kb or barttin compromise currents through heteromeric channels. Currents can be stimulated further by mutating a proline-tyrosine (PY) motif on barttin. This work describes the first known beta-subunit for CLC chloride channels and reveals that heteromers formed by ClC-K and barttin are crucial for renal salt reabsorption and potassium recycling in the inner ear.
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Proteínas de Transporte de Anión , Canales de Cloruro/metabolismo , Cloruros/metabolismo , Oído Interno/metabolismo , Riñón/metabolismo , Proteínas de la Membrana/metabolismo , Potasio/metabolismo , Absorción , Animales , Síndrome de Bartter/metabolismo , Línea Celular , Túbulos Renales/metabolismo , Proteínas de la Membrana/genética , Subunidades de Proteína , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , XenopusRESUMEN
Antenatal Bartter syndrome (aBS) comprises a heterogeneous group of autosomal recessive salt-losing nephropathies. Identification of three genes that code for renal transporters and channels as responsible for aBS has resulted in new insights into renal salt handling, diuretic action and blood-pressure regulation. A gene locus of a fourth variant of aBS called BSND, which in contrast to the other forms is associated with sensorineural deafness (SND) and renal failure, has been mapped to chromosome 1p. We report here the identification by positional cloning, in a region not covered by the human genome sequencing projects, of a new gene, BSND, as the cause of BSND. We examined ten families with BSND and detected seven different mutations in BSND that probably result in loss of function. In accordance with the phenotype, BSND is expressed in the thin limb and the thick ascending limb of the loop of Henle in the kidney and in the dark cells of the inner ear. The gene encodes a hitherto unknown protein with two putative transmembrane alpha-helices and thus might function as a regulator for ion-transport proteins involved in aBS, or else as a new transporter or channel itself.
Asunto(s)
Síndrome de Bartter/genética , Pérdida Auditiva Sensorineural/genética , Proteínas de la Membrana/genética , Mutación/genética , Insuficiencia Renal/genética , Animales , Síndrome de Bartter/complicaciones , Canales de Cloruro , Cromosomas Humanos Par 1/genética , Clonación Molecular , Análisis Mutacional de ADN , Exones/genética , Femenino , Perfilación de la Expresión Génica , Haplotipos/genética , Pérdida Auditiva Sensorineural/complicaciones , Humanos , Hibridación in Situ , Riñón/metabolismo , Riñón/patología , Masculino , Ratones , Datos de Secuencia Molecular , Mapeo Físico de Cromosoma , Polimorfismo Conformacional Retorcido-Simple , Diagnóstico Prenatal , ARN Mensajero/genética , ARN Mensajero/metabolismo , Insuficiencia Renal/complicacionesRESUMEN
Juvenile nephronophthisis type 1 is caused by mutations of NPHP1, the gene encoding for nephrocystin. The function of nephrocystin is presently unknown, but the presence of a Src homology 3 domain and its recently described interaction with p130(Cas) suggest that nephrocystin is part of the focal adhesion signaling complex. We generated a nephrocystin-specific antiserum and analyzed the interaction of native nephrocystin with endogenous proteins. Immunoprecipitation of nephrocystin revealed that nephrocystin forms protein complexes with p130(Cas), proline-rich tyrosine kinase 2 (Pyk2), and tensin, indicating that these proteins participate in a common signaling pathway. Expression of nephrocystin resulted in phosphorylation of Pyk2 on tyrosine 402 as well as activation of downstream mitogen-activated protein kinases, such as ERK1 and ERK2. Our findings suggest that nephrocystin helps to recruit Pyk2 to cell matrix adhesions, thereby initiating phosphorylation of Pyk2 and Pyk2-dependent signaling. A lack of functional nephrocystin may compromise Pyk2 signaling in a subset of renal epithelial cells.
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Proteínas de Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Procesamiento Proteico-Postraduccional , Proteínas Tirosina Quinasas/metabolismo , Proteínas/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Western Blotting , Células Cultivadas , Proteína Sustrato Asociada a CrK , Proteínas del Citoesqueleto , Células Epiteliales/metabolismo , Quinasa 2 de Adhesión Focal , Humanos , Túbulos Renales Colectores/citología , Sistema de Señalización de MAP Quinasas , Sustancias Macromoleculares , Proteínas de la Membrana , Ratones , Fosforilación , Fosfotirosina/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Proteína p130 Similar a la del Retinoblastoma , Tensinas , Dominios Homologos srcRESUMEN
Autosomal dominant medullary cystic kidney disease (MCKD) is an adult onset tubulointerstitial nephropathy that leads to salt wasting and end-stage renal failure. A gene locus (MCKD1) has been mapped on chromosome 1q21. Here we report on a large MCKD1 family of British origin linked to the MCKD1 locus. Haplotype analysis performed with markers spanning the previously reported critical MCKD1 region allowed for the refinement of this interval to 4 cM by definition of D1S305 as a new proximal flanking marker. Furthermore, we constructed a yeast artificial chromosome, P1-related artificial chromosome, and bacterial artificial chromosome contig of this region, which is only sparsely covered by the Human Genome Sequencing Project. This enabled us to map numerous expressed sequence tags within the critical interval. This physical and partial transcriptional map of the MCKD1 region is a powerful tool for the identification of positional and functional candidate genes for MCKD1 and will help to identify the disease-causing gene.
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Riñón Poliquístico Autosómico Dominante/genética , Cromosomas Humanos Par 1/genética , Mapeo Contig , ADN/genética , Salud de la Familia , Femenino , Ligamiento Genético , Haplotipos , Humanos , Masculino , Repeticiones de Microsatélite , Linaje , Mapeo Físico de Cromosoma , Riñón Poliquístico Autosómico Dominante/patología , Transcripción GenéticaRESUMEN
UNLABELLED: We report on an 11-year-old girl with a large lymphangioma involving the lower third of the abdominal wall, the mons pubis, both labia majora, the perianal region and extending into the pelvic bones. Because of an increasing lymphorrhea from the cutaneous lesions resulting in considerable discomfort and skin infections, the patient sought medical advice. After lymphological check-up excluded the existence of a chylous reflux, the patient was presented at a multidisciplinary medical council. A palliative surgical treatment was recommended consisting of the resection of the most affected suprapubic region and the coverage of the resulting tissue defect with a gracilis myocutaneous flap. Postoperatively, a venous stasis at the tip of the skin paddle developed, which was relieved by the use of leeches and required secondary closure. Despite these complications, the surgical intervention yielded an acceptable cosmetic result, a diminution of lymphorrhea and hence subjectively some relief. CONCLUSION: Due to the variability of lymphangiomas, an assessment by a multidisciplinary consultation is proposed. With respect to therapy, the use of a myocutaneous flap represents one of the therapeutic options for large cutaneous lymphangiomas.
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Músculos Abdominales/cirugía , Genitales Femeninos/cirugía , Linfangioma/cirugía , Niño , Femenino , Humanos , Trasplante de Piel , Colgajos QuirúrgicosRESUMEN
Juvenile or type 1 nephronophthisis (NPH1), an autosomal recessive cystic kidney disease, represents the most common genetic cause of end-stage renal disease in the first two decades of life. Because the disease is caused by large homozygous deletions of the NPHP1 gene in approximately 66% of patients with nephronophthisis, molecular genetic testing offers a method for the definite diagnosis of NPH1 and avoids the invasive procedure of renal biopsy. We recently developed an algorithm for molecular genetic diagnosis of NPH1 that efficiently detects homozygous deletions. However, a major limitation remained for the detection of heterozygous deletions that cause NPH1 in combination with point mutations at the other NPHP1 allele. Because a partial sequence from the NPHP1 region recently became available through the Human Genome Projects, we exploited this information to develop novel polymorphic markers from this genetic region for the detection of heterozygous deletions of NPHP1, thus bridging the diagnostic gap. Five novel polymorphic microsatellites positioned within the large common NPHP1 deletion were generated. Two multiplex polymerase chain reaction sets using two and three polymorphic markers from the NPHP1 deletion region together with one positive control marker allowed four different diagnostic problems to be solved in one diagnostic setup: (1) detection of the classic homozygous deletion of NPH1, (2) detection of a rare smaller homozygous deletion of NPH1, (3) testing for a heterozygous deletion, and (4) potential exclusion of linkage to NPHP1. The newly generated multiplex marker sets will greatly enhance the efficacy of molecular diagnostics in NPH through improved detection of heterozygous deletions.
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Enfermedades Renales Quísticas/genética , Proteínas/genética , Proteínas Adaptadoras Transductoras de Señales , Niño , Proteínas del Citoesqueleto , ADN/genética , Salud de la Familia , Femenino , Eliminación de Gen , Marcadores Genéticos , Haplotipos , Heterocigoto , Humanos , Enfermedades Renales Quísticas/diagnóstico , Masculino , Proteínas de la Membrana , Linaje , Polimorfismo GenéticoRESUMEN
Among identified adhesion molecules, the L-selectin on neutrophils enables the first step of leukocyte adherence to activated endothelial cells. To allow firm adhesion of neutrophils, L-selectin is then split off the cell membrane. It was hypothetized that an increase of the constitutively high serum level of soluble L-selectin may indicate an ongoing pathological neutrophil sequestration to the endothelial cells associated with activation and injury of the cells. To evaluate this hypothesis, sL-selectin serum levels and neutrophil L-selectin expression of healthy volunteers (group A, n = 15), as well as of surgical patients, were investigated. Group B (n = 26) included patients subjected to elective limb surgery (mean operation time, 122 min), and group C (n = 45) comprised trauma patients. sL-selectin serum levels were measured daily over a 14-day period. Neutrophil L-selectin expression was evaluated by FACS analysis using the humanized anti-L-selectin antibody HuDreg 55 over a period of 3 days at minimum in both experimental groups. The binding of sL-selectin to endothelial cells was also examined in vitro. Elective limb surgery resulted in lower pre- and post-operative sL-selectin plasma levels (800-1,000 ng/mL) compared to healthy volunteers (1,100-1,200 ng/mL) with insignificant changes throughout the study period. Trauma patients revealed even lower sL-selectin levels (400-600 ng/mL). When these patients were discriminated by the multiple organ dysfunction (MOD) score of Moore in +MOD (n = 9, ISS = 31.7) and -MOD (n = 36, ISS = 25.0), a significant difference became evident. In +MOD patients sL-selectin levels remained on a low basis of 350 ng/mL, whereas in -MOD patients the initial low sL-selectin level subsequently rose to 800 ng/mL, similar to that of elective surgery patients. FACS analysis revealed a significant drop in neutrophil L-selectin expression 24 h after trauma compared to normal. Also, +MOD and -MOD patients were significantly discriminated by the L-selectin expression at this time. The in vitro studies revealed evidence for binding of sL-selectin to endothelial cells independently on the presence of neutrophils. According to our data, increasing severity of the post-operative/posttraumatic course is associated with decreasing sL-selectin serum levels and also reduced neutrophil L-selectin expression. In view of the in vitro results, this probably indicates competitive enhanced binding of sL-selectin to endothelial cells, thus masking the elevated activation of neutrophils and their ability for endothelial adherence.
Asunto(s)
Regulación de la Expresión Génica , Selectina L/biosíntesis , Neutrófilos/metabolismo , Heridas y Lesiones/inmunología , Adolescente , Adulto , Adhesión Celular , Células Cultivadas , Quimiotaxis de Leucocito , Procedimientos Quirúrgicos Electivos , Endotelio Vascular/patología , Citometría de Flujo , Humanos , Selectina L/sangre , Selectina L/genética , Persona de Mediana Edad , Insuficiencia Multiorgánica/etiología , Traumatismo Múltiple/sangre , Traumatismo Múltiple/genética , Traumatismo Múltiple/inmunología , Neutrófilos/patología , Estudios Prospectivos , Proteínas Recombinantes/metabolismo , Índice de Severidad de la Enfermedad , Solubilidad , Heridas y Lesiones/sangre , Heridas y Lesiones/genéticaRESUMEN
Nephronophthisis (NPH) and medullary cystic kidney disease (MCKD) constitute a group of renal cystic diseases, which share a common characteristic renal histologic triad of tubular basement membrane disintegration, tubular atrophy with cyst development, and interstitial cell infiltration with fibrosis. The different disease variants lead to chronic renal failure with onset at characteristic age ranges for recessive NPH and dominant MCKD. There is extensive gene locus heterogeneity with at least three different loci for nephronophthisis (NPHP1, NPHP2, and NPHP3) and two different loci for MCKD (MCKD1 and MCKD2). Juvenile nephronophthisis, in addition, can be associated with extrarenal organ involvement. We have identified by positional cloning the gene (NPHP1) for juvenile nephronophthisis (NPH1), as a first step towards understanding the pathogenesis of this disease group. Its gene product, nephrocystin, is a novel protein, which contains a src-homology 3 (SH3) domain. We put forward a hypothesis that the pathogenesis of NPH might be related to signaling processes at focal adhesions (the contact points between cells and extracellular matrix) and/or adherens junctions (the contact points between cells).
Asunto(s)
Enfermedades Renales Quísticas/patología , Niño , Humanos , Enfermedades Renales Quísticas/diagnóstico , Enfermedades Renales Quísticas/genética , Médula Renal/patologíaRESUMEN
BACKGROUND: A new type of nephronophthisis (NPH) has been recently identified in a large Venezuelan kindred: adolescent nephronophthisis (NPH3) causes end-stage renal disease (ESRD) at a median age of 19 years. The responsible gene (NPHP3) maps to 3q21-q22. NPH3 shares with juvenile nephronophthisis (NPH1) the same disease manifestations such as polyuria, polydipsia, and secondary enuresis. Histopathological findings consist of tubular basement membrane changes, cysts at the corticomedullary junction, and a chronic sclerosing tubulointerstitial nephropathy. The only difference is a younger age at ESRD in NPH1 (median age of 13 years) when compared with NPH3. METHODS: In order to evaluate whether there might be a fourth locus of isolated nephronophthisis, we studied eight NPH families without extrarenal disease manifestations and without linkage to the NPH1 locus (NPHP1) on chromosome 2q12-q13. ESRD was reached at ages ranging from 7 to 33 years. Individuals were haplotyped with microsatellites covering the genetic locus of NPHP3. Infantile NPH (NPH2) was excluded in all families by the clinical history and histological findings. RESULTS: In four of the examined families haplotype analysis was compatible with linkage to the NPHP3 locus. In one of these families identity by descent was observed. In contrast, in another four families linkage was excluded for NPHP3. CONCLUSION: Four NPH-families were neither linked to NPHP1 nor to NPHP3, indicating further genetic heterogeneity within the group of nephronophthisis. The finding of further genetic heterogeneity in NPH has important implications for genetic counselling.