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1.
Genet Med ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30425301

RESUMO

PURPOSE: We aimed to assess the biological and clinical significance of the human cysteine protease inhibitor cystatin M/E, encoded by the CTS6 gene, in diseases of human hair and skin. METHODS: Exome and Sanger sequencing was performed to reveal the genetic cause in two related patients with hypotrichosis. Immunohistochemical, biophysical, and biochemical measurements were performed on patient skin and 3D-reconstructed skin from patient-derived keratinocytes. RESULTS: We identified a homozygous variant c.361C>T (p.Gln121*), resulting in a premature stop codon in exon 2 of CST6 associated with hypotrichosis, eczema, blepharitis, photophobia and impaired sweating. Enzyme assays using recombinant mutant cystatin M/E protein, generated by site-directed mutagenesis, revealed that this p.Gln121* variant was unable to inhibit any of its three target proteases (legumain and cathepsins L and V). Three-dimensional protein structure prediction confirmed the disturbance of the protease/inhibitor binding sites of legumain and cathepsins L and V in the p.Gln121* variant. CONCLUSION: The herein characterized autosomal recessive hypotrichosis syndrome indicates an important role of human cystatin M/E in epidermal homeostasis and hair follicle morphogenesis.

2.
Hum Mol Genet ; 27(17): 3029-3045, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29878199

RESUMO

Genomics methodologies have significantly improved elucidation of Mendelian disorders. The combination with high-throughput functional-omics technologies potentiates the identification and confirmation of causative genetic variants, especially in singleton families of recessive inheritance. In a cohort of 99 individuals with abnormal Golgi glycosylation, 47 of which being unsolved, glycomics profiling was performed of total plasma glycoproteins. Combination with whole-exome sequencing in 31 cases revealed a known genetic defect in 15 individuals. To identify additional genetic factors, hierarchical clustering of the plasma glycomics data was done, which indicated a subgroup of four patients that shared a unique glycomics signature of hybrid type N-glycans. In two siblings, compound heterozygous mutations were found in SLC10A7, a gene of unknown function in human. These included a missense mutation that disrupted transmembrane domain 4 and a mutation in a splice acceptor site resulting in skipping of exon 9. The two other individuals showed a complete loss of SLC10A7 mRNA. The patients' phenotype consisted of amelogenesis imperfecta, skeletal dysplasia, and decreased bone mineral density compatible with osteoporosis. The patients' phenotype was mirrored in SLC10A7 deficient zebrafish. Furthermore, alizarin red staining of calcium deposits in zebrafish morphants showed a strong reduction in bone mineralization. Cell biology studies in fibroblasts of affected individuals showed intracellular mislocalization of glycoproteins and a defect in post-Golgi transport of glycoproteins to the cell membrane. In contrast to yeast, human SLC10A7 localized to the Golgi. Our combined data indicate an important role for SLC10A7 in bone mineralization and transport of glycoproteins to the extracellular matrix.

3.
Hum Genet ; 2018 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-29740699

RESUMO

Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease genes.

4.
Am J Hum Genet ; 101(2): 300-310, 2017 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-28777935

RESUMO

Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and no previous genetic diagnosis. We identified 7 rare non-synonymous variants in 7 of 20 genes and performed Sanger sequence validation in affected probands and parental samples. De novo variants were found only in SLC1A2 (aka EAAT2 or GLT1) (c.244G>A [p.Gly82Arg]) and YWHAG (aka 14-3-3γ) (c.394C>T [p.Arg132Cys]), highlighting the potential cause of EE in 5% (2/42) of subjects. Seven additional subjects with de novo variants in SLC1A2 (n = 1) and YWHAG (n = 6) were subsequently identified through online tools. We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy, and we provide additional support for the prior assignment of SLC1A2. Hence, in silico modeling of brain co-expression is an efficient method for nominating EE-associated genes to further elucidate the disorder's etiology and genotype-phenotype correlations.


Assuntos
Proteínas 14-3-3/genética , Predisposição Genética para Doença , Proteínas de Transporte de Glutamato da Membrana Plasmática/genética , Espasmos Infantis/genética , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Exoma/genética , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Fenótipo , Adulto Jovem
5.
Am J Med Genet A ; 167A(3): 461-75, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25604898

RESUMO

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n = 64), others having SEMD (n = 5), Kniest dysplasia (n = 7), spondyloperipheral dysplasia (n = 2), or Torrance-like dysplasia (n = 2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders.


Assuntos
Colágeno Tipo II/genética , Mutação , Osteocondrodisplasias/congênito , Fenótipo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Radiografia , Adulto Jovem
6.
J Clin Endocrinol Metab ; 99(4): 1107-11, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24423337

RESUMO

CONTEXT: Although the baby growing in its mother's womb needs calcium for skeletal development, osteoporosis and fractures very rarely occur during pregnancy. CASE PRESENTATION: A 27-year-old woman in the seventh month of her first pregnancy contracted midthoracic back pain after lifting an object. The pain was attributed to her pregnancy, but it remained postpartum. Her past medical history was uneventful, except for severely reduced vision of her left eye since birth. Family history revealed that her maternal grandmother had postmenopausal osteoporosis and her half-brother had three fractures during childhood after minor trauma. Her height was 1.58 m; she had no blue sclerae or joint hyperlaxity. Laboratory examination including serum calcium, phosphate, alkaline phosphatase, creatinine, ß-carboxyterminal cross-linking telopeptide of type I collagen, 25-hydroxyvitamin D, and TSH was normal. Multiple thoracic vertebral fractures were diagnosed on x-ray examination, and dual-energy x-ray absorptiometry scanning showed severe osteoporosis (Z-scores: L2-L4, -5.6 SD; femur neck, -3.9 SD). DNA analyses revealed two compound heterozygous missense mutations in LRP5. The patient's mother carried one of the LRP5 mutations and was diagnosed with osteoporosis. Her half-brother, treated with cabergoline for a microprolactinoma, also had osteoporosis of the lumbar spine on dual-energy x-ray absorptiometry and carried the same LRP5 mutation. The patient was treated with risedronate for 2.5 years. Bone mineral density and back pain improved. She stopped bisphosphonate use 6 months before planning a second pregnancy. CONCLUSION: Our patient was diagnosed with osteoporosis pseudoglioma syndrome/familial exudative vitreoretinopathy. Potential underlying genetic causes should be considered in pregnancy-associated osteoporosis with implications for patients and relatives. More studies regarding osteoporosis treatment preceding conception are desirable.


Assuntos
Osteogênese Imperfeita/diagnóstico , Osteoporose/complicações , Fraturas por Osteoporose/complicações , Complicações na Gravidez/diagnóstico , Fraturas da Coluna Vertebral/complicações , Vitreorretinopatia Proliferativa/diagnóstico , Adulto , Feminino , Humanos , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/genética , Osteoporose/diagnóstico , Osteoporose/genética , Fraturas por Osteoporose/diagnóstico , Fraturas por Osteoporose/genética , Linhagem , Gravidez , Complicações na Gravidez/genética , Fraturas da Coluna Vertebral/genética , Vitreorretinopatia Proliferativa/complicações , Vitreorretinopatia Proliferativa/genética
7.
N Engl J Med ; 369(16): 1529-36, 2013 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-24088043

RESUMO

Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. The bone-regulatory properties of PLS3 were supported by in vivo analyses in zebrafish. Furthermore, in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found. This variant was also associated with a risk of fracture among elderly heterozygous women that was two times as high as that among noncarriers, which indicates that genetic variation in PLS3 is a novel etiologic factor involved in common, multi-factorial osteoporosis.


Assuntos
Fraturas Ósseas/genética , Glicoproteínas de Membrana/genética , Proteínas dos Microfilamentos/genética , Osteoporose/genética , Adulto , Animais , Densidade Óssea/genética , Remodelação Óssea/genética , Criança , Pré-Escolar , Feminino , Fraturas Ósseas/etiologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Heterozigoto , Humanos , Masculino , Mutação , Osteoporose/complicações , Linhagem , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto Jovem , Peixe-Zebra
8.
Am J Med Genet C Semin Med Genet ; 160C(3): 205-16, 2012 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-22791362

RESUMO

From data collected via a large international collaborative study, we have constructed a growth chart for patients with molecularly confirmed congenital spondylo-epiphyseal dysplasia (SEDC) and other COL2A1 related dysplasias. The growth chart is based on longitudinal height measurements of 79 patients with glycine substitutions in the triple-helical domain of COL2A1. In addition, measurements of 27 patients with other molecular defects, such as arginine to cysteine substitutions, splice mutations, and mutations in the C-terminal propeptide have been plotted on the chart. Height of the patients progressively deviate from that of normal children: compared to normal WHO charts, the mean length/height is -2.6 SD at birth, -4.2 SD at 5 years, and -5.8 SD in adulthood. The mean adult height (male and female combined) of patients with glycine substitutions in the triple-helical region is 138.2 cm but there is a large variation. Patients with glycine to cysteine substitutions tend to cluster within the upper part of the chart, while patients with glycine to serine or valine substitutions are situated between +1 SD and -1 SD. Patients with carboxy-terminal glycine substitutions tend to be shorter than patients with amino-terminal substitutions, while patients with splice mutations are relatively tall. However, there are exceptions and specific mutations can have a strong or a relatively mild negative effect on growth. The observation of significant difference in adult height between affected members of the same family indicates that height remains a multifactorial trait even in the presence of a mutation with a strong dominant effect.


Assuntos
Colágeno Tipo II/genética , Gráficos de Crescimento , Mutação/genética , Osteocondrodisplasias/genética , Substituição de Aminoácidos/genética , Estatura/genética , Criança , Códon/genética , Colágeno Tipo II/química , Feminino , Humanos , Masculino , Osteocondrodisplasias/diagnóstico por imagem , Estrutura Secundária de Proteína , Processamento de RNA/genética , Radiografia , Adulto Jovem
9.
Am J Med Genet A ; 158A(2): 292-7, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22140078

RESUMO

We describe a newborn girl with multiple congenital anomalies and abnormal phenotype comprising underdeveloped corpus callosum with ventriculomegaly, chorioretinal atrophy, pulmonary arterial hypertension, annular pancreas, horseshoe kidney, asymmetric limb and chest anomalies, spinal segmentation defects, hypertrichosis, and unusual face with large anterior fontanel, high anterior hairline, broad forehead, mildly underdeveloped midface, hypertelorism, depressed nasal bridge, short and upturned nose, large mouth, retrognathia, and large and malformed ears. Work-up included cytogenetic studies of lymphocytes and skin fibroblasts, subtelomere Multiplex Ligation-dependent Probe Amplification (MLPA), whole-genome oligo-array, and molecular analysis of SETBP1 and NSDHL: no abnormalities were found. Mucopolysaccharide urinary excretion was elevated. Results of metabolic studies for sterol and peroxisomal abnormalities in fibroblasts were normal. Additional electronic microscopy studies in skin fibroblasts did not show evidence for storage in fibroblasts or lysosomal changes. Nosologic considerations allowed exclusion of Schinzel-Giedion and Urioste syndrome. This condition seems not to have been described before; a segregating Mendelian mutation is assumed.


Assuntos
Anormalidades Múltiplas/diagnóstico , Corpo Caloso/patologia , Diagnóstico Diferencial , Deformidades Congênitas dos Membros/patologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Corpo Caloso/crescimento & desenvolvimento , Anormalidades Craniofaciais/diagnóstico , Criptorquidismo/diagnóstico , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Feminino , Fibroblastos/metabolismo , Glicosaminoglicanos/urina , Deformidades Congênitas da Mão/diagnóstico , Humanos , Recém-Nascido , Deficiência Intelectual/diagnóstico , Linfócitos/citologia , Ductos Paramesonéfricos/anormalidades , Mutação , Unhas Malformadas/diagnóstico , Fenótipo , Polidactilia/diagnóstico
10.
Hum Mutat ; 31(8): E1587-93, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20648631

RESUMO

Cleidocranial Dysplasia (CCD) is an autosomal dominant skeletal disorder characterized by hypoplastic or absent clavicles, increased head circumference, large fontanels, dental anomalies, and short stature. Hand malformations are also common. Mutations in RUNX2 cause CCD, but are not identified in all CCD patients. In this study we screened 135 unrelated patients with the clinical diagnosis of CCD for RUNX2 mutations by sequencing analysis and demonstrated 82 mutations 48 of which were novel. By quantitative PCR we screened the remaining 53 unrelated patients for copy number variations in the RUNX2 gene. Heterozygous deletions of different size were identified in 13 patients, and a duplication of the exons 1 to 4 of the RUNX2 gene in one patient. Thus, heterozygous deletions or duplications affecting the RUNX2 gene may be present in about 10% of all patients with a clinical diagnosis of CCD which corresponds to 26% of individuals with normal results on sequencing analysis. We therefore suggest that screening for intragenic deletions and duplications by qPCR or MLPA should be considered for patients with CCD phenotype in whom DNA sequencing does not reveal a causative RUNX2 mutation.


Assuntos
Displasia Cleidocraniana/genética , Deleção de Genes , Análise Mutacional de DNA , Heterozigoto , Humanos , Reação em Cadeia da Polimerase
11.
Eur J Hum Genet ; 18(9): 999-1005, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20531442

RESUMO

Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000. The etiology of HPE is extremely heterogeneous and can be teratogenic or genetic. We screened four known HPE genes in a Dutch cohort of 86 non-syndromic HPE index cases, including 53 family members. We detected 21 mutations (24.4%), 3 in SHH, 9 in ZIC2 and 9 in SIX3. Eight mutations involved amino-acid substitutions, 7 ins/del mutations, 1 frame-shift, 3 identical poly-alanine tract expansions and 2 gene deletions. Pathogenicity of mutations was presumed based on de novo character, predicted non-functionality of mutated proteins, segregation of mutations with affected family-members or combinations of these features. Two mutations were reported previously. SNP array confirmed detected deletions; one spanning the ZIC2/ZIC5 genes (approx. 100 kb) the other a 1.45 Mb deletion including SIX2/SIX3 genes. The mutation percentage (24%) is comparable with previous reports, but we detected significantly less mutations in SHH: 3.5 vs 10.7% (P=0.043) and significantly more in SIX3: 10.5 vs 4.3% (P=0.018). For TGIF1 and ZIC2 mutation the rate was in conformity with earlier reports. About half of the mutations were de novo, one was a germ line mosaic. The familial mutations displayed extensive heterogeneity in clinical manifestation. Of seven familial index patients only two parental carriers showed minor HPE signs, five were completely asymptomatic. Therefore, each novel mutation should be considered as a risk factor for clinically manifest HPE, with the caveat of reduced clinical penetrance.


Assuntos
Proteínas do Olho/genética , Proteínas Hedgehog/genética , Holoprosencefalia/genética , Proteínas de Homeodomínio/genética , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Feminino , Humanos , Masculino , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único
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