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1.
Artigo em Inglês | MEDLINE | ID: mdl-31710781

RESUMO

EML1 encodes the protein Echinoderm microtubule-associated protein-like 1 or EMAP-1 that binds to the microtubule complex. Mutations in this gene resulting in complex brain malformations have only recently been published with limited clinical descriptions. We provide further clinical and imaging details on three previously published families, and describe two novel unrelated individuals with a homozygous partial EML1 deletion and a homozygous missense variant c.760G>A, p.(Val254Met), respectively. From review of the clinical and imaging data of eight individuals from five families with biallelic EML1 variants, a very consistent imaging phenotype emerges. The clinical syndrome is characterized by mainly neurological features including severe developmental delay, drug-resistant seizures and visual impairment. On brain imaging there is megalencephaly with a characteristic ribbon-like subcortical heterotopia combined with partial or complete callosal agenesis and an overlying polymicrogyria-like cortical malformation. Several of its features can be recognized on prenatal imaging especially the abnormaly formed lateral ventricles, hydrocephalus (in half of the cases) and suspicion of a neuronal migration disorder. In conclusion, biallelic EML1 disease-causing variants cause a highly specific pattern of congenital brain malformations, severe developmental delay, seizures and visual impairment.

3.
Genet Med ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31316167

RESUMO

PURPOSE: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing. METHODS: In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups. RESULTS: The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups. CONCLUSIONS: Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.

4.
BMC Med Genet ; 18(1): 79, 2017 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-28747166

RESUMO

BACKGROUND: Fumarate hydratase (FH) deficiency is a rare autosomal recessive disorder which results in a major defect in cellular metabolism. It presents in infancy with progressive encephalopathy, hypotonia, seizures and failure to thrive and is often fatal in childhood. It is caused by mutations in the FH gene (1q42.1) that result in deficiency of the citric acid cycle enzyme fumarate hydratase, resulting in accumulation of fumaric acid. Heterozygous germline mutations in the FH gene predispose to an aggressive autosomal dominant inherited early-onset kidney cancer syndrome: hereditary leiomyomatosis and renal cell cancer (HLRCC). CASE PRESENTATION: Cascade FH mutation screening enabled the early diagnosis of a renal tumour in an asymptomatic parent of a child with fumarate hydratase deficiency, resulting in timely and possibly life-saving treatment. CONCLUSION: While the theoretical risk of kidney cancer in parents of children with recessive fumarate hydratase deficiency is well recognized, to our knowledge this is the first report of a kidney tumour being detected in a parent by screening performed for this indication. This underscores the importance of offering lifelong kidney surveillance to such parents and other heterozygous relatives of children born with fumarate hydratase deficiency.


Assuntos
Carcinoma de Células Renais/genética , Fumarato Hidratase/deficiência , Fumarato Hidratase/genética , Neoplasias Renais/genética , Erros Inatos do Metabolismo/genética , Hipotonia Muscular/genética , Transtornos Psicomotores/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Detecção Precoce de Câncer , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Lactente , Neoplasias Renais/complicações , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/patologia , Hipotonia Muscular/complicações , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/patologia , Transtornos Psicomotores/complicações , Transtornos Psicomotores/diagnóstico , Transtornos Psicomotores/patologia
5.
Case Rep Pediatr ; 2017: 9682803, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28523199

RESUMO

Phosphatase and tensin homolog (PTEN) is the protein encoded by the PTEN gene (10q23.3). PTEN mutations are related to a variety of rare diseases referred to collectively as PTEN hamartoma tumor syndromes (PHTS), which include Cowden Syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus Syndrome, and Proteus-like syndrome. These diseases are associated with an increased risk of malignancy and for this reason an accurate and early diagnosis is essential in order to institute cancer surveillance. PTEN is a regulator of growth and homeostasis in immune system cells, although there are limited data describing immune dysregulation caused by PTEN mutations. We describe a case of PHTS syndrome caused by a de novo mutation in PTEN detected using a targeted next generation sequencing (NGS) gene panel which was instigated for workup of cutaneous vasculitis. We highlight the diagnostic utility of this approach and that mutations in PTEN may be associated with immune-dysregulatory features such as vasculitis in young children.

7.
Horm Res Paediatr ; 88(2): 172-178, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28359061

RESUMO

BACKGROUND: Coexistence of congenital adrenal hyperplasia (CAH) and congenital hypothyroidism (CH) due to TG mutation in the same non-consanguineous family is rare. CASE SERIES: We report 4 siblings born to unrelated parents, the father being an asymptomatic carrier of homozygous p.V281L and heterozygous p.I172N CYP21A2 mutations. Sibling 1 had salt-wasting CAH (CYP21A2 genotype Intron 2 splice/p.I172N and p.V281L). She also had CH (TG genotype p.R296/ p.T1416Rfs*30) and learning difficulties. Poor compliance and morbid obesity resulted in short stature, precocious puberty, hirsutism, amenorrhoea, insulin insensitivity and a possible adrenal adenoma. Sibling 3 (CYP21A2 and TG genotype similar to sibling 1) is a boy presenting with salt-wasting CAH, CH, and developmental delay. He was overweight and underwent precocious puberty. Although siblings 2 and 4 (both females) share the same CYP21A2 genotype (Intron 2 splice/p.V281L), the former only had biochemical evidence of CAH, while the latter presented at 9.8 years of age with a history of pubarche at 7 years and advanced bone age. CONCLUSIONS: We report the unusual occurrence of 2 rare autosomal recessive diseases, CAH and CH. Our cases highlight the phenotypic variability of CAH and CH due to TG mutations, even within a single family, and illustrate the importance of optimal disease control.
.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Hipotireoidismo Congênito/genética , Tireoglobulina/genética , Adolescente , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Criança , Hipotireoidismo Congênito/complicações , Hipotireoidismo Congênito/tratamento farmacológico , Feminino , Humanos , Masculino , Mutação , Cooperação do Paciente , Linhagem , Fenótipo
9.
Nat Genet ; 49(2): 223-237, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27992417

RESUMO

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.


Assuntos
Distonia/genética , Histona-Lisina N-Metiltransferase/genética , Mutação/genética , Adolescente , Proteínas de Ligação a DNA/genética , Feminino , Histona Metiltransferases , Histonas/genética , Humanos , Lisina/genética , Masculino , Metilação , Proteínas Nucleares/genética
10.
Nat Genet ; 48(10): 1185-92, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27571260

RESUMO

Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.


Assuntos
Doenças de Pequenos Vasos Cerebrais/genética , Leucoencefalopatias/genética , Mutação , RNA Nucleolar Pequeno/genética , Adolescente , Adulto , Calcinose/genética , Calcinose/patologia , Linhagem Celular , Doenças de Pequenos Vasos Cerebrais/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 17 , Estudos de Coortes , Cistos/genética , Cistos/patologia , Exoma , Feminino , Ligação Genética , Genoma Humano , Humanos , Lactente , Leucoencefalopatias/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Adulto Jovem
11.
Am J Med Genet A ; 170A(5): 1115-26, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26971886

RESUMO

Cerebro-Costo-Mandibular syndrome (CCMS) is a rare autosomal dominant condition comprising branchial arch-derivative malformations with striking rib-gaps. Affected patients often have respiratory difficulties, associated with upper airway obstruction, reduced thoracic capacity, and scoliosis. We describe a series of 12 sporadic and 4 familial patients including 13 infants/children and 3 adults. Severe micrognathia and reduced numbers of ribs with gaps are consistent findings. Cleft palate, feeding difficulties, respiratory distress, tracheostomy requirement, and scoliosis are common. Additional malformations such as horseshoe kidney, hypospadias, and septal heart defect may occur. Microcephaly and significant developmental delay are present in a small minority of patients. Key radiological findings are of a narrow thorax, multiple posterior rib gaps and abnormal costo-transverse articulation. A novel finding in 2 patients is bilateral accessory ossicles arising from the hyoid bone. Recently, specific mutations in SNRPB, which encodes components of the major spliceosome, have been found to cause CCMS. These mutations cluster in an alternatively spliced regulatory exon and result in altered SNRPB expression. DNA was available from 14 patients and SNRPB mutations were identified in 12 (4 previously reported). Eleven had recurrent mutations previously described in patients with CCMS and one had a novel mutation in the alternative exon. These results confirm the specificity of SNRPB mutations in CCMS and provide further evidence for the role of spliceosomal proteins in craniofacial and thoracic development.


Assuntos
Anormalidades Múltiplas/genética , Fissura Palatina/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Costelas/anormalidades , Proteínas Centrais de snRNP/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Criança , Pré-Escolar , Fissura Palatina/complicações , Fissura Palatina/fisiopatologia , Éxons , Feminino , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Masculino , Micrognatismo/complicações , Micrognatismo/fisiopatologia , Mutação , Costelas/crescimento & desenvolvimento , Costelas/fisiopatologia , Escoliose/complicações , Escoliose/genética , Escoliose/fisiopatologia , Spliceossomos/genética
12.
Am J Hum Genet ; 98(2): 373-81, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26833328

RESUMO

Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Mutação , Ubiquitina Tiolesterase/genética , Adolescente , Sequência de Bases , Criança , Pré-Escolar , Atresia das Cóanas/diagnóstico , Atresia das Cóanas/genética , Deficiências do Desenvolvimento/diagnóstico , Feminino , Genes Ligados ao Cromossomo X , Testes Genéticos , Humanos , Deficiência Intelectual/diagnóstico , Dados de Sequência Molecular , Fenótipo , Ubiquitina Tiolesterase/metabolismo , Inativação do Cromossomo X , Adulto Jovem
13.
J Med Genet ; 51(10): 659-68, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25125236

RESUMO

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. METHODS: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. RESULTS: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as 'NIPBL-like'. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases. CONCLUSIONS: Future diagnostic testing in 'mutation-negative' CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.


Assuntos
Síndrome de Lange/genética , Heterogeneidade Genética , Mosaicismo , Face/patologia , Estudos de Associação Genética , Humanos , Mutação , Fenótipo
15.
Nat Genet ; 46(1): 70-6, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24241535

RESUMO

Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase 1 (PSS1). PSS1 is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS1. We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism.


Assuntos
Anormalidades Múltiplas/genética , Mutação , Transferases de Grupos Nitrogenados/genética , Adolescente , Animais , Células Cultivadas , Criança , Nanismo , Embrião não Mamífero , Feminino , Fibroblastos/metabolismo , Humanos , Hiperostose , Masculino , Dados de Sequência Molecular , Transferases de Grupos Nitrogenados/metabolismo , Fosfatidilserinas/biossíntese , Fosfatidilserinas/genética , Síndrome , Peixe-Zebra/embriologia , Peixe-Zebra/genética
16.
Pediatr Nephrol ; 26(8): 1331-4, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21597970

RESUMO

Sotos syndrome is characterized by overgrowth, a typical facial appearance, and learning difficulties. It is caused by heterozygous mutations, including deletions, of NSD1 located at chromosome 5q35. Here we report two unrelated cases of Sotos syndrome associated with nephrocalcinosis. One patient also had idiopathic infantile hypercalcemia. Genetic investigations revealed heterozygous deletions at 5q35 in both patients, encompassing NSD1 and SLC34A1 (NaPi2a). Mutations in SLC34A1 have previously been associated with hypercalciuria/nephrolithiasis. Our cases suggest a contiguous gene deletion syndrome including NSD1 and SLC34A1 and provide a potential genetic basis for idiopathic infantile hypercalcemia.


Assuntos
Hipercalcemia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Nefrocalcinose/genética , Proteínas Nucleares/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIa/genética , Síndrome de Sotos/complicações , Síndrome de Sotos/genética , Cromossomos Humanos Par 5/genética , Hibridização Genômica Comparativa , Feminino , Deleção de Genes , Humanos , Hipercalcemia/fisiopatologia , Lactente , Recém-Nascido , Mutação , Nefrocalcinose/fisiopatologia , Síndrome de Sotos/fisiopatologia
17.
Arch Dis Child ; 96(10): 954-9, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20656736

RESUMO

PURPOSE: Sex chromosome trisomies (SCTs) are found on amniocentesis in 2.3-3.7 per 1000 same-sex births, yet there is a limited database on which to base a prognosis. Autism has been described in postnatally diagnosed cases of Klinefelter syndrome (XXY karyotype), but the prevalence in non-referred samples, and in other trisomies, is unclear. The authors recruited the largest sample including all three SCTs to be reported to date, including children identified on prenatal screening, to clarify this issue. DESIGN: Parents of children with a SCT were recruited either via prenatal screening or via a parental support group, to give a sample of 58 XXX, 19 XXY and 58 XYY cases. Parents were interviewed using the Vineland Adaptive Behavior Scales and completed questionnaires about the communicative development of children with SCTs and their siblings (42 brothers and 26 sisters). RESULTS: Rates of language and communication problems were high in all three trisomies. Diagnoses of autism spectrum disorder (ASD) were found in 2/19 cases of XXY (11%) and 11/58 XYY (19%). After excluding those with an ASD diagnosis, communicative profiles indicative of mild autistic features were common, although there was wide individual variation. CONCLUSIONS: Autistic features have not previously been remarked upon in studies of non-referred samples with SCTs, yet the rate is substantially above population levels in this sample, even when attention is restricted to early-identified cases. The authors hypothesise that X-linked and Y-linked neuroligins may play a significant role in the aetiology of communication impairments and ASD.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos do Desenvolvimento da Linguagem/genética , Aberrações dos Cromossomos Sexuais , Trissomia , Criança , Transtornos Globais do Desenvolvimento Infantil/psicologia , Educação Especial , Escolaridade , Feminino , Humanos , Cariotipagem , Transtornos do Desenvolvimento da Linguagem/terapia , Terapia da Linguagem , Masculino , Diagnóstico Pré-Natal/métodos , Psicometria , Fonoterapia
18.
Best Pract Res Clin Endocrinol Metab ; 24(2): 335-54, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20541156

RESUMO

Disorder of sex development (DSD) presents a unique challenge, both diagnostically and in terms of acute and longer-term management. These are relatively rare conditions usually requiring a multidisciplinary approach from the outset and the involvement of a tertiary centre for assessment and management recommendations. This article describes the structure of the multidisciplinary team (MDT) at our centre, with contributions from key members of the team regarding their individual roles. The focus is on the newborn referred for assessment of ambiguous genitalia, rather than on individuals who present in the adolescent period or at other times, although the same MDT involvement is likely to be required. The approach to the initial assessment and management is discussed and the subsequent diagnosis and follow-up presented, with emphasis on the importance of careful transition and long-term support.


Assuntos
Transtornos do Desenvolvimento Sexual/terapia , Saúde Holística , Equipe de Assistência ao Paciente , Adolescente , Adulto , Criança , Transtornos do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/psicologia , Endocrinologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Biologia Molecular , Equipe de Assistência ao Paciente/ética , Encaminhamento e Consulta , Urologia
19.
Clin Dysmorphol ; 18(3): 131-4, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19339878

RESUMO

We describe a female infant with a diaphragmatic hernia and nasopharyngeal teratoma. The case is compared with two previous reports of this combination of features. We suggest that this can no longer be considered a random association but instead represents the emergence of a distinct syndrome of which this case represents the third report.


Assuntos
Hérnia Diafragmática/diagnóstico , Neoplasias Nasofaríngeas/diagnóstico , Teratoma/diagnóstico , Índice de Apgar , Feminino , Humanos , Recém-Nascido , Imagem por Ressonância Magnética , Gravidez , Síndrome , Tomografia Computadorizada por Raios X
20.
Hum Mutat ; 30(2): E330-7, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18853461

RESUMO

Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome is a multi-system autosomal recessive disorder caused by germline mutations in VPS33B. The detection of germline VPS33B mutations removes the need for diagnostic organ biopsies (these carry a>50% risk of life-threatening haemorrhage due to platelet dysfunction); however, VPS33B mutations are not detectable in approximately 25% of patients. In order further to define the molecular basis of ARC we performed mutation analysis and mRNA and protein studies in patients with a clinical diagnosis of ARC. Here we report novel mutations in VPS33B in patients from Eastern Europe and South East Asia. One of the mutations was present in 7 unrelated Korean patients. Reduced expression of VPS33B and cellular phenotype was detected in fibroblasts from patients clinically diagnosed with ARC with and without known VPS33B mutations. One mutation-negative patient was found to have normal mRNA and protein levels. This patient's clinical condition improved and he is alive at the age of 2.5 years. Thus we show that all patients with a classical clinical course of ARC had decreased expression of VPS33B whereas normal VPS33B expression was associated with good prognosis despite initial diagnosis of ARC.


Assuntos
Artrogripose/complicações , Artrogripose/diagnóstico , Colestase/complicações , Colestase/diagnóstico , Nefropatias/complicações , Nefropatias/diagnóstico , Artrogripose/etnologia , Pré-Escolar , Colestase/etnologia , Fibroblastos/metabolismo , Fibroblastos/ultraestrutura , Humanos , Lactente , Nefropatias/etnologia , Masculino , Mutação/genética , Síndrome , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
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