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2.
Genet Med ; 21(5): 1058-1064, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30245510

RESUMO

PURPOSE: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes. METHODS: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed. RESULTS: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants. CONCLUSIONS: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.


Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Deleção Cromossômica , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Proteínas de Membrana/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , ATPases Vacuolares Próton-Translocadoras/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 16 , Estudos de Coortes , Feminino , Proteínas Ativadoras de GTPase , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Síndrome , Adulto Jovem
3.
Genet Med ; 21(11): 2521-2531, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31092906

RESUMO

PURPOSE: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established. METHODS: Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease. RESULTS: The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration. CONCLUSION: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.


Assuntos
Doenças Musculares/genética , Fator de Transcrição PAX7/genética , Adolescente , Alelos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Desenvolvimento Muscular , Músculo Esquelético/metabolismo , Doenças Musculares/etiologia , Mioblastos , Fator de Transcrição PAX7/metabolismo , Linhagem , Regeneração , Células Satélites de Músculo Esquelético/metabolismo , Fatores de Transcrição/genética , Sequenciamento do Exoma/métodos
4.
J Med Genet ; 50(11): 740-4, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23687350

RESUMO

BACKGROUND: Mutations in TSC1 or TSC2 cause the tuberous sclerosis complex (TSC), a disorder characterised by the development of hamartomas or benign tumours in various organs as well as the variable presence of epilepsy, intellectual disability (ID) and autism. TSC1, TSC2 and the recently described protein TBC1D7 form a complex that inhibits mTORC1 signalling and limits cell growth. Although it has been proposed that mutations in TBC1D7 might also cause TSC, loss of its function has not yet been documented in humans. METHODS AND RESULTS: We used homozygosity mapping and exome sequencing to study a consanguineous family with ID and megalencephaly but without any specific features of TSC. We identified only one rare coding variant, c.538delT:p.Y180fsX1 in TBC1D7, in the regions of homozygosity shared by the affected siblings. We show that this mutation abolishes TBC1D7 expression and is associated with increased mTORC1 signalling in cells of the affected individuals. CONCLUSIONS: Our study suggests that disruption of TBC1D7 causes ID but without the other typical features found in TSC. Although megalencephaly is not commonly observed in TSC, it has been associated with mTORC1 activation. Our observation thus reinforces the relationship between this pathway and the development of megalencephaly.


Assuntos
Proteínas de Transporte/genética , Deficiência Intelectual/genética , Megalencefalia/genética , Esclerose Tuberosa/genética , Criança , Pré-Escolar , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Mutação , Linhagem
5.
Eur J Paediatr Neurol ; 30: 25-28, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33387902

RESUMO

Heterozygous pathogenic WAC variants cause Desanto-Shinawi syndrome; affected patients have dysmorphic features, developmental impairment and behavioral abnormalities. Seizures are reported in one quarter, including tonic-clonic, absence, and febrile seizures. This study aimed to better understand the phenotypic spectrum of epilepsy and development in Desanto-Shinawi syndrome. We identified four children with seizures and pathogenic WAC variants, including two siblings. All had global developmental impairment with language affected most severely; two had diagnoses of childhood apraxia of speech and two had autism spectrum disorder. Seizure onset age ranged from six months to 14 years. Seizures always occurred from sleep and were focal impaired awareness with motor features in three patients, with one having bilateral tonic-clonic seizures of suspected focal onset. Two patients had spontaneous seizure resolution without treatment, and the remaining two were well-controlled on monotherapy. EEG was normal in two patients; one had focal right frontal spikes in drowsiness and sleep while the last had independent centrotemporal spikes from both hemispheres, activated in sleep. All patients had heterozygous truncating pathogenic WAC variants, with negative parental testing. The findings in this cohort of patients suggest that epilepsy in Desanto-Shinawi syndrome is usually focal and self-limited, and may fall within the epilepsy-aphasia spectrum.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Apraxias/genética , Epilepsias Parciais/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Transtorno do Espectro Autista/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino
6.
Bone ; 109: 225-231, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29307777

RESUMO

The large majority of cases of the autosomal dominant human disease fibrodysplasia ossificans progressiva (FOP) are caused by gain-of-function Arg206His mutations in the BMP type I receptor ACVR1 (ALK2). The Arg206His mutation is located in the GS domain of the type I receptor. This region is normally phosphorylated by the BMP type II receptor, which activates the type I receptor to phosphorylate its substrate, the signal transducer Smad1/5/8. A small subset of patients with FOP carry variant mutations in ACVR1 altering Gly328 to Trp, Glu or Arg. Since these mutations lie outside the GS domain, the mechanism through which ACVR1 Gly328 mutations cause disease remains unclear. We used a zebrafish embryonic development assay to test the signaling of human ACVR1 Gly328 mutant receptors comparing them to the Arg206His mutant. In this assay increased or decreased BMP pathway activation alters dorsal-ventral axial patterning, providing a sensitive assay for altered BMP signaling levels. We expressed the human ACVR1 Gly328 mutant receptors in zebrafish embryos to investigate their signaling activities. We found that all ACVR1 Gly328 human mutations ventralized wild-type embryos and could partially rescue Bmp7-deficient embryos, indicating that these mutant receptors can activate BMP signaling in a BMP ligand-independent manner. The degree of ventralization or rescue was similar among all three Gly328 mutants. Smad1/5 phosphorylation, a readout of BMP receptor signaling, was mildly increased by ACVR1 Gly328 mutations. Gene expression analyses demonstrate expanded ventral and reciprocal loss of dorsal cell fate markers. This study demonstrates that Gly328 mutants increase receptor activation and BMP ligand-independent signaling through Smad phosphorylation.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas/metabolismo , Miosite Ossificante/metabolismo , Peixe-Zebra/metabolismo , Receptores de Ativinas Tipo I/genética , Receptores de Ativinas Tipo I/metabolismo , Animais , Receptores de Proteínas Morfogenéticas Ósseas/genética , Humanos , Mutação , Miosite Ossificante/genética , Ligação Proteica/genética , Ligação Proteica/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Peixe-Zebra/genética
7.
Hum Genet ; 119(6): 649-58, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16738948

RESUMO

Medullary cystic kidney disease type 1 (MCKD1) is an autosomal dominant, tubulo-interstitial nephropathy that causes renal salt wasting and end-stage renal failure in the fourth to seventh decade of life. MCKD1 was localized to chromosome 1q21. We demonstrated haplotype sharing and confirmed the telomeric border by a recombination of D1S2624 in a Belgian kindred. Since the causative gene has been elusive, high resolution haplotype analysis was performed in 16 kindreds. Clinical data and blood samples of 257 individuals (including 75 affected individuals) from 26 different kindreds were collected. Within the defined critical region mutational analysis of 37 genes (374 exons) in 23 MCKD1 patients was performed. In addition, for nine kindreds RT-PCR analysis for the sequenced genes was done to screen for mutations activating cryptic splice sites. We found consistency with the haplotype sharing hypothesis in an additional nine kindreds, detecting three different haplotype subsets shared within a region of 1.19 Mb. Mutational analysis of all 37 positional candidate genes revealed sequence variations in 3 different genes, AK000210, CCT3, and SCAMP3, that were segregating in each affected kindred and were not found in 96 healthy individuals, indicating, that a single responsible gene causing MCKD1 remains elusive. This may point to involvement of different genes within the MCKD1 critical region.


Assuntos
Mapeamento Cromossômico , Haplótipos , Rim em Esponja Medular/genética , Análise Mutacional de DNA , Humanos , Repetições de Microssatélites/genética
8.
Pediatr Nephrol ; 19(12): 1340-8, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15338398

RESUMO

Primary steroid-resistant nephrotic syndrome (SRNS) is characterized by childhood onset of proteinuria and progression to end-stage renal disease. In 26% of cases it is caused by recessive mutations in NPHS2 (podocin). Congenital nephrotic syndrome (CNS) is caused by mutations in NPHS1 (nephrin) or NPHS2. In three families mutations in NPHS1 and NPHS2 had been reported to occur together, and these tri-allelic mutations were implicated in genotype/phenotype correlations. To further test the hypothesis of tri-allelism, we examined a group of 62 unrelated patients for NPHS1 mutations, who were previously shown to have NPHS2 mutations; 15 of 62 patients had CNS. In addition, 12 CNS patients without NPHS2 mutation were examined for NPHS1 mutations. Mutational analysis yielded three different groups. (1) In 48 patients with two recessive NPHS2 mutations (11 with CNS), no NPHS1 mutation was detected, except for 1 patient, who had one NPHS1 mutation only. This patient was indistinguishable clinically and did not have CNS. (2) In 14 patients with one NPHS2 mutation only (4 with CNS), we detected two additional recessive NPHS1 mutations in the 4 patients with CNS. They all carried the R229Q variant of NPHS2. The CNS phenotype may be sufficiently explained by the presence of two NPHS1 mutations. (3) In 12 patients without NPHS2 mutation (all with CNS), we detected two recessive NPHS1 mutations in 11 patients, explaining their CNS phenotype. We report ten novel mutations in the nephrin gene. Our data do not suggest any genotype/phenotype correlation in the 5 patients with mutations in both the NPHS1 and the NPHS2 genes.


Assuntos
Proteínas de Membrana/genética , Mutação , Proteínas/genética , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Fenótipo
9.
Kidney Int ; 64(5): 1580-7, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14531790

RESUMO

BACKGROUND: Autosomal-dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulointerstitial nephropathy that causes renal salt wasting, hyperuricemia, gout, and end-stage renal failure in the fifth decade of life. The chromosomal locus for MCKD2 was localized on chromosome 16p12. Within this chromosomal region, Uromodulin (UMOD) was located as a candidate gene. UMOD encodes the Tamm-Horsfall protein. By sequence analysis, one group formerly excluded UMOD as the disease-causing gene. In contrast, recently, another group described mutations in the UMOD gene as responsible for MCKD2 and familial juvenile hyperuricemic nephropathy (FJHN). METHODS: Haplotype analysis for linkage to MCKD2 was performed in 25 MCKD families. In the kindreds showing linkage to the MCKD2 locus on chromosome 16p12, mutational analysis of the UMOD gene was performed by exon polymerase chain reaction (PCR) and direct sequencing. RESULTS: In 19 families, haplotype analysis was compatible with linkage to the MCKD2 locus. All these kindreds were examined for mutations in the UMOD gene. In three different families, three novel heterozygous mutations in the UMOD gene were found and segregated with the phenotype in affected individuals. Mutations were found only in exon 4. CONCLUSION: We confirm the UMOD gene as the disease-causing gene for MCKD2. All three novel mutations were found in the fourth exon of UMOD, in which all mutations except one (this is located in the neighboring exon 5) published so far are located. These data point to a specific role of exon 4 encoded sequence of UMOD in the generation of the MCKD2 renal phenotype.


Assuntos
Fator de Crescimento Epidérmico/genética , Mucoproteínas/genética , Rim Policístico Autossômico Dominante/genética , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Fator de Crescimento Epidérmico/química , Éxons/genética , Feminino , Ligação Genética , Haplótipos , Humanos , Masculino , Dados de Sequência Molecular , Mucoproteínas/química , Família Multigênica , Linhagem , Fenótipo , Estrutura Terciária de Proteína , Uromodulina
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