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1.
J Matern Fetal Neonatal Med ; 32(3): 502-511, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28954562

RESUMO

Arthrogryposis multiplex congenita (AMC) refers to the development of multiple joint contractures affecting two or more areas of the body prior to birth. It affects approximately 1 in 3000 individuals, mostly reported in individuals of Asian, African and European descent with equal incidence in males and females. Arthrogryposis is associated with over 400 medical conditions and 350 known genes with considerable variability in phenotypic expression. The primary underlying mechanism is decreased fetal movement during development. Prenatal imaging is crucial in early diagnosis by identifying fetal movement limitations and the presence of club foot or joint contractures. Postnatal autopsy confirms the diagnosis and extent of associated congenital anomalies and provides a valuable source of DNA material. Molecular methods are particularly useful in delineating novel gene mutations, locus heterogeneity and phenotype genotype correlation. Prenatal evaluation with early diagnosis via image scanning and further genetic surveillance give the opportunity for family counseling concerning future pregnancy management and expected neonatal morbidity and mortality.


Assuntos
Artrogripose/diagnóstico , Artrogripose/patologia , Artrogripose/epidemiologia , Artrogripose/genética , Feminino , Estudos de Associação Genética , Humanos , Fenótipo , Gravidez , Ultrassonografia Pré-Natal
2.
Clin Dysmorphol ; 28(1): 17-21, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30303820

RESUMO

Glycogen storage disease IV (GSD IV), caused by a defect in GBE1, is a clinically heterogeneous disorder. A classical hepatic form and a neuromuscular form have been described. The severe neuromuscular form presents as a fetal akinesia deformation sequence or a congenital subtype. We ascertained three unrelated families with fetuses/neonates who presented with fetal akinesia deformation sequence to our clinic for genetic counseling. We performed a detailed clinical evaluation, exome sequencing, and histopathology examination of two fetuses and two neonates from three unrelated families presenting with these perinatally lethal neuromuscular forms of GSD IV. Exome sequencing in the affected fetuses/neonates identified four novel pathogenic variants (c.1459G>T, c.144-1G>A, c.1680C>G, and c.1843G>C) in GBE1 (NM_000158). Histopathology examination of tissues from the affected fetuses/neonate was consistent with the diagnosis. Here, we add three more families with the severe perinatally lethal neuromuscular forms of GSD IV to the GBE1 mutation spectrum.


Assuntos
Artrogripose/enzimologia , Artrogripose/genética , Sistema da Enzima Desramificadora do Glicogênio/genética , Doença de Depósito de Glicogênio Tipo IV/enzimologia , Doença de Depósito de Glicogênio Tipo IV/genética , Mutação/genética , Doenças Neuromusculares/enzimologia , Doenças Neuromusculares/genética , Artrogripose/patologia , Sequência de Bases , Feminino , Feto/patologia , Doença de Depósito de Glicogênio Tipo IV/patologia , Humanos , Recém-Nascido , Masculino , Doenças Neuromusculares/patologia , Linhagem
3.
Int J Mol Sci ; 19(8)2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30071673

RESUMO

Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. VEGFC, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4) and important for lymph vessel development during lymphangiogenesis, has been associated with a specific subtype of primary lymphedema. Through Sanger sequencing of a proband with bilateral congenital pedal edema resembling Milroy disease, we identified a novel mutation (NM_005429.2; c.361+5G>A) in VEGFC. The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18). The mutation leads to a loss of the entire VEGF-homology domain and the C-terminus. Expression of this Vegfc variant in the zebrafish floorplate showed that the splice-site variant significantly reduces the biological activity of the protein. Our findings confirm that the splice-site variant, c.361+5G>A, causes the primary lymphedema phenotype in the proband. We examine the mutations and clinical phenotypes of the previously reported cases to review the current knowledge in this area.


Assuntos
Artrogripose/genética , Fissura Palatina/genética , Pé Torto Equinovaro/genética , Mutação da Fase de Leitura , Deformidades Congênitas da Mão/genética , Processamento de RNA/genética , Fator C de Crescimento do Endotélio Vascular/genética , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Artrogripose/metabolismo , Artrogripose/patologia , Pré-Escolar , Fissura Palatina/metabolismo , Fissura Palatina/patologia , Pé Torto Equinovaro/metabolismo , Pé Torto Equinovaro/patologia , Feminino , Deformidades Congênitas da Mão/metabolismo , Deformidades Congênitas da Mão/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Domínios Proteicos , Fator C de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
4.
Int J Mol Med ; 42(4): 2238-2246, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30015832

RESUMO

The present study aimed to identify the molecular basis of the arthrogryposis­renal dysfunction­cholestasis (ARC) syndrome, which is caused by mutations in the vacuolar protein sorting 33 homolog B (VPS33B) gene. The microarray dataset GSE83192, which contained six liver tissue samples from VPS33B knockout mice and four liver tissue samples from control mice, was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were screened by the Limma package in R software. The DEGs most relevant to ARC were selected via weighted gene co­expression network analysis to construct a protein­protein interaction (PPI) network. In addition, module analysis was performed for the PPI network using the Molecular Complex Detection function. Functional and pathway enrichment analyses were also performed for DEGs in the PPI network. Potential drugs for ARC treatment were predicted using the Connectivity Map database. In total, 768 upregulated and 379 downregulated DEGs were detected in the VPS33B knockout mice, while three modules were identified from the PPI network constructed. The DEGs in module 1 (CD83, IL1B and TLR2) were mainly involved in the positive regulation of cytokine production and the Toll­like receptor (TLR) signaling pathway. The DEGs in module 2 (COL1A1 and COL1A2) were significantly enriched with respect to cellular component organization, extracellular matrix­receptor interactions and focal adhesion. The DEGs in module 3 (ABCG8 and ABCG3) were clearly associated with sterol absorption and transport. Furthermore, mercaptopurine was identified to be a potential drug (connectivity score=­0.939) for ARC treatment. In conclusion, the results of the current study may help to further understand the pathology of ARC, and the DEGs identified in these modules may serve as therapeutic targets.


Assuntos
Artrogripose , Colestase , Redes Reguladoras de Genes , Insuficiência Renal , Transdução de Sinais/genética , Animais , Artrogripose/genética , Artrogripose/metabolismo , Artrogripose/patologia , Colestase/genética , Colestase/metabolismo , Colestase/patologia , Camundongos , Camundongos Knockout , Insuficiência Renal/genética , Insuficiência Renal/metabolismo , Insuficiência Renal/patologia
5.
Brain Dev ; 40(9): 760-767, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29803542

RESUMO

OBJECTIVE: To reveal a molecular lesion in the ZC4H2 gene in a Japanese family with arthrogryposis multiplex congenita (AMC) and intellectual disability (ID), and to characterize clinical features of patients with ZC4H2 gene mutations through a literature review. PATIENTS: The probands are male siblings. The elder brother is an 11-year-old boy who showed AMC and ID and frequent postprandial hypoglycemia since 3 years of age. The younger brother also showed AMC, ID, and subclinical postprandial hypoglycemia. The boys' mother also showed a minor malformation of the left toes. METHOD AND RESULT: Using Sanger sequencing, a hemizygous one base substitution designated c.627G > C, which is predicted to substitute asparagine for lysine at amino acid residue 209 (K209N), was identified in the siblings. The mother was heterozygous for this mutation. In silico analysis predicted K209N to be a constituent of a motif required for subcellular localization of the ZC4H2 protein in the nucleus. Transient expression studies of subcellular localization in COS-7 cells showed that compared to the wild-type protein, the transport of the mutant protein into the nucleus was inhibited, thus confirming K209N as a molecular lesion in this family. The literature reviews revealed postprandial hypoglycemia as a new clinical feature that should be considered in ZC4H2 gene-mutation disorders. CONCLUSION: A Japanese family with AMC and ID caused by a novel ZC4H2 gene mutation was reported. Hypoglycemia should be considered one of the features in this disorder.


Assuntos
Artrogripose/genética , Proteínas de Transporte/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Artrogripose/patologia , Artrogripose/fisiopatologia , Proteínas de Transporte/metabolismo , Linhagem Celular , Criança , Humanos , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Masculino , Fenótipo , Irmãos
6.
Biochim Biophys Acta Mol Basis Dis ; 1864(5 Pt A): 1609-1621, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29409756

RESUMO

Mutations in VPS33B and VIPAS39 cause the severe multisystem disorder Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome. Amongst other symptoms, patients with ARC syndrome suffer from severe ichthyosis. Roles for VPS33B and VIPAR have been reported in lysosome-related organelle biogenesis, integrin recycling, collagen homeostasis and maintenance of cell polarity. Mouse knockouts of Vps33b or Vipas39 are good models of ARC syndrome and develop an ichthyotic phenotype. We demonstrate that the skin manifestations in Vps33b and Vipar deficient mice are histologically similar to those of patients with ARC syndrome. Histological, immunofluorescent and electron microscopic analysis of Vps33b and Vipar deficient mouse skin biopsies and isolated primary cells showed that epidermal lamellar bodies, which are essential for skin barrier function, had abnormal morphology and the localisation of lamellar body cargo was disrupted. Stratum corneum formation was affected, with increased corneocyte thickness, decreased thickness of the cornified envelope and reduced deposition of lipids. These defects impact epidermal homeostasis and lead to abnormal barrier formation causing the skin phenotype in Vps33b and Vipar deficient mice and patients with ARC syndrome.


Assuntos
Artrogripose , Colestase , Epiderme , Insuficiência Renal , Proteínas de Transporte Vesicular , Animais , Artrogripose/genética , Artrogripose/metabolismo , Artrogripose/patologia , Colestase/genética , Colestase/metabolismo , Colestase/patologia , Modelos Animais de Doenças , Epiderme/metabolismo , Epiderme/patologia , Humanos , Camundongos , Camundongos Knockout , Insuficiência Renal/genética , Insuficiência Renal/metabolismo , Insuficiência Renal/patologia , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
7.
Clin Genet ; 93(1): 160-163, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28317099

RESUMO

Arthrogryposis multiplex congenita (AMC) is heterogeneous group of disorders characterized by non-progressive joint contractures from birth that involve more than 1 part of the body. There are various etiologies for AMC including genetic and environmental depends on the specific type, however, for most types, the cause is not fully understood. We previously reported large Israeli Arab kindred consisting of 16 patients affected with AMC neuropathic type, and mapped the locus to a 5.5 cM interval on chromosome 5qter. Using whole exome sequencing, we have now identified homozygous pathogenic variant in the ERGIC1 gene within the previously defined linked region. ERGIC1 encodes a cycling membrane protein which has a possible role in transport between endoplasmic reticulum and Golgi. We further show that this mutation was absent in more than 200 samples of healthy unrelated individuals of the Israeli Arab population. Thus, our findings expand the spectrum of hereditary AMC and suggest that abnormalities in protein trafficking may underlie AMC-related disorders.


Assuntos
Artrogripose/genética , Predisposição Genética para Doença/genética , Mutação , Proteínas de Transporte Vesicular/genética , Sequência de Aminoácidos , Árabes , Artrogripose/patologia , Sequência de Bases , Consanguinidade , Feminino , Homozigoto , Humanos , Israel , Masculino , Linhagem , Sequenciamento Completo do Exoma/métodos
8.
Brain Dev ; 40(4): 334-338, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29254829

RESUMO

Arthrogryposis multiplex congenita (AMC) is characterized by heterogeneous multiple congenital contractures appearing at birth. Mutations in X-linked zinc-finger gene ZC4H2 were recently identified in some families and individuals with variable forms of AMC associated with dysmorphic signs, intellectual disability and spastic paresis. We present a non-consanguineous Japanese female presenting AMC with severe intellectual disability and spastic quadriplegia who also had progressive brain atrophy. Microarray-based comparative genomic hybridization identified 395 kb microdeletions at Xq11.2 which only included ZC4H2 gene. Previous reports showed that affected females have lesser symptoms and slight abnormality on brain MRI compared to male due to X-inactivation. Our case, however, showed severe manifestation than as ever reported as well as progressive diffuse brain atrophy, which implicated contribution of other genetic or environmental factors or extremely skewed X inactivation.


Assuntos
Artrogripose/genética , Encefalopatias/genética , Proteínas de Transporte/genética , Deficiência Intelectual/genética , Artrogripose/diagnóstico por imagem , Artrogripose/patologia , Atrofia/diagnóstico por imagem , Atrofia/genética , Atrofia/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encefalopatias/diagnóstico por imagem , Encefalopatias/patologia , Pré-Escolar , Feminino , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia
9.
Acta Neuropathol Commun ; 5(1): 83, 2017 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-29132416

RESUMO

Endothelin-converting enzyme-like 1 (ECEL1, also termed DINE in rodents), a membrane-bound metalloprotease, has been identified as a gene responsible for distal arthrogryposis (DA). ECEL1-mutated DA is generally characterized by ocular phenotypes in addition to the congenital limb contractures that are common to all DA subtypes. Until now, the consequences of the identified pathogenic mutations have remained incompletely understood because of a lack of detailed phenotypic analyses in relevant mouse models. In this study, we generated a new knock-in mouse strain that carries an ECEL1/DINE pathogenic G607S missense mutation, based on a previous study reporting atypical DA hindlimb phenotypes in two siblings with the mutation. We compared the morphological phenotypes of G607S knock-in mice with C760R knock-in mice that we previously established. Both C760R and G607S knock-in mouse embryos showed similar axonal arborization defects with normal trajectory patterns from the spinal cord to the target hindlimb muscles, as well as axon guidance defects of the abducens nerves. Intriguingly, distinct phenotypes in DINE protein localization and mRNA expression were identified in these knock-in mouse lines. For G607S, DINE mRNA and protein expression was decreased or almost absent in motor neurons. In the C760R mutant mice DINE was expressed and localized in the somata of motor neurons but not in axons. Our mutant mouse data suggest that ECEL1/DINE G607S and C760R mutations both lead to motor innervation defects as primary causes in ECEL1-mutated congenital contracture disorders. However, the functional consequences of the two mutations are distinct, with loss of axonal transport of ECEL1/DINE in C760R mutants and mRNA expression deficits in G607S mutants.


Assuntos
Artrogripose/genética , Artrogripose/fisiopatologia , Metaloendopeptidases/genética , Mutação de Sentido Incorreto/genética , Nervo Abducente/patologia , Animais , Artrogripose/patologia , Transporte Axonal/genética , Axônios/patologia , Modelos Animais de Doenças , Glicosídeo Hidrolases/farmacologia , Membro Posterior/inervação , Metaloendopeptidases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Músculo Esquelético/metabolismo , RNA Mensageiro/metabolismo , Medula Espinal/embriologia , Medula Espinal/metabolismo
10.
Am J Med Genet A ; 173(10): 2725-2730, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28840640

RESUMO

Disorders of brain formation can occur from pathogenic variants in various alpha and beta tubulin genes. Heterozygous pathogenic variants in the beta tubulin isotype A gene, TUBB2A, have been recently implicated in brain malformations, seizures, and developmental delay. Limited information is known regarding the phenotypic spectrum associated with pathogenic variants in this gene given the rarity of the condition. We report the sixth individual with a de novo heterozygous TUBB2A pathogenic variant, who presented with a severe neurological phenotype along with unique features of arthrogryposis multiplex congenita, optic nerve hypoplasia, dysmorphic facial features, and vocal cord paralysis, thereby expanding the gene-related phenotype.


Assuntos
Artrogripose/genética , Encefalopatias/genética , Deficiências do Desenvolvimento/genética , Mutação de Sentido Incorreto , Tubulina (Proteína)/genética , Artrogripose/complicações , Artrogripose/patologia , Encefalopatias/complicações , Encefalopatias/patologia , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/patologia , Evolução Fatal , Predisposição Genética para Doença , Humanos , Masculino
11.
Am J Med Genet A ; 173(10): 2798-2802, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28815864

RESUMO

Interstitial deletions of the short and long arms of chromosome 5 are rare cytogenetic abnormalities. The 5p distal deletion is a genetic disorder characterized by a high-pitched cat-like cry, microcephaly, epicanthal folds, micrognathia, severe intellectual disability and motor delays. Previously, more than 46 patients with the 5q deletion have been reported. Here, we report de novo interstitial deletions involving 5p14.1-p15.2 and 5q14.3-q23.2 in a patient with multiple congenital abnormalities, including blepharophimosis, arthrogryposis, short neck, round face, pelvic kidney, agenesis of the corpus callosum, and clubfoot. The deletions were characterized using GTG banding and aCGH microarray analysis. Concurrent 5p and 5q interstitial deletions in humans have not been previously reported. We also discussed the relationship between the 5q deleted region and clubfeet.


Assuntos
Artrogripose/genética , Blefarofimose/genética , Deleção Cromossômica , Cromossomos Humanos Par 5 , Pé Torto Equinovaro/genética , Anormalidades Congênitas/genética , Adulto , Artrogripose/complicações , Artrogripose/patologia , Blefarofimose/complicações , Blefarofimose/patologia , Pré-Escolar , Pé Torto Equinovaro/complicações , Pé Torto Equinovaro/patologia , Anormalidades Congênitas/patologia , Feminino , Humanos , Lactente , Masculino , Prognóstico
12.
Invest Radiol ; 52(12): 741-746, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28723713

RESUMO

OBJECTIVES: The aim of this study was to evaluate whether high-resolution brachial plexus (BP) magnetic resonance neurography (MRN) is capable of (1) distinguishing patients with compressive neuropathy or noncompressive plexopathy from age- and sex-matched controls, (2) discriminating between patients with compressive neuropathy and noncompressive plexopathy, and (3) detecting spatial lesion patterns suggesting somatotopic organization of the BP. MATERIALS AND METHODS: Thirty-six patients (50.9 ± 12.7 years) with clinical symptoms, nerve conduction studies, and needle electromyography findings suggestive of brachial plexopathy and 36 control subjects matched for age and sex (50.8 ± 12.6 years) underwent high-resolution MRN of the BP. Lesion determination and localization was performed by 2 blinded neuroradiologists at the anatomical levels of the plexus trunks and cords. RESULTS: By applying defined criteria of structural plexus lesions on high-resolution MRN, all patients were correctly rated as affected, whereas 34 of 36 controls were correctly rated as unaffected by independent and blinded reading from 2 neuroradiologists with overall good to excellent interrater reliability. In all cases, plexopathies with a compressive etiology (n = 12) were correctly distinguished from noncompressive plexopathies with inflammatory origin (n = 24). Pathoanatomical contiguity of lesion from trunk into cord level allowed recognition of distinct somatotopical patterns of fascicular involvement, which correlated closely with the spatial distribution of clinical symptoms and electrophysiological data. CONCLUSIONS: Brachial plexus MRN is highly accurate for differentiating patients with symptomatic plexopathy from healthy controls and for distinguishing patients with compressive neuropathy and noncompressive plexopathy. Furthermore, BP MRN revealed evidence for somatotopic organization of the BP. Therefore, as an addition to functional information of electrodiagnostic studies, anatomical information gained by BP MRN may help to improve the efficiency and accuracy of patient care.


Assuntos
Artrogripose/diagnóstico por imagem , Neuropatias do Plexo Braquial/diagnóstico por imagem , Plexo Braquial/diagnóstico por imagem , Neuropatia Hereditária Motora e Sensorial/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Artrogripose/patologia , Plexo Braquial/patologia , Neuropatias do Plexo Braquial/patologia , Diagnóstico Diferencial , Eletromiografia , Feminino , Neuropatia Hereditária Motora e Sensorial/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes
13.
Medicine (Baltimore) ; 96(19): e6922, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28489810

RESUMO

RATIONALE: Hereditary neuropathy with liability to pressure palsy (HNPP) is an episodic, multifocal neuropathy, with a typical clinical presentation of recurrent transient pressure palsies, which is induced by a PMP22 deletion. Another neuropathy caused by a PMP22 duplication is Charcot-Marie-Tooth disease type 1A (CMT1A). PMP22 is a gene coding a protein called peripheral myelin protein 22 (PMP22), which plays an essential role in the formation and maintenance of compact myelin. Coexistence of type 2 diabetes mellitus (T2DM) and CMT1A has been reported in many work, however HNPP patients with T2DM are rare, and comorbidity of HNPP and psoriasis has not been reported previously. Electrophysiological features of HNPP has been found progressing with aging. Patient concerns: Here we present a 20-year-old man who exhibited lower extremity weakness and foot drop as the initial manifestation. DIAGNOSES: HNPP was diagnosed on the basis of clinical features, positive sural nerve biopsy findings, and genetic testing results. Moreover, physical examination, blood/urine glucose test, and diabetes-related autoantibodies investigations demonstrated that he had psoriasis and T2DM. The electrophysiological manifestations revealed profound demyelinating injuries and axonal injuries in distal peripheral nerves and facial nerves, which were more severe than general HNPP cases. INTERVENTIONS: The young patient was treated with continuous subcutaneous insulin infusion and blood glucose monitoring, and then transferred to oral acarbose therapy. The psoriatic lesions were treated with calcipotriol ointment. OUTCOMES: In the follow-up, the right leg weakness was alleviated, and his gait was improved. LESSONS: The findings indicate that diabetes mellitus may have an impact on the severity of HNPP. Physicians should consider that worsening of symptoms might result from newly diagnosed diabetes mellitus while treating patients with HNPP.


Assuntos
Artrogripose/complicações , Diabetes Mellitus Tipo 2/complicações , Neuropatia Hereditária Motora e Sensorial/complicações , Psoríase/complicações , Artrogripose/diagnóstico , Artrogripose/patologia , Artrogripose/terapia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/terapia , Diagnóstico Diferencial , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Neuropatia Hereditária Motora e Sensorial/patologia , Neuropatia Hereditária Motora e Sensorial/terapia , Humanos , Masculino , Psoríase/diagnóstico , Psoríase/patologia , Psoríase/terapia , Adulto Jovem
15.
Pediatr Infect Dis J ; 36(5): 500-501, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28403053
16.
Am J Med Genet A ; 173(4): 1119-1123, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28328131

RESUMO

We describe the clinical and whole genome sequencing (WGS) study of a non-consanguineous Italian family in which two siblings, a boy and a girl, manifesting a severe epileptic encephalopathy (EE) with skeletal abnormalities, carried novel SLC35A3 compound heterozygous mutations. Both siblings exhibited infantile spasms, associated with focal, and tonic vibratory seizures from early infancy. EEG recordings showed a suppression-burst (SB) pattern and multifocal paroxysmal activity in both. In addition both had quadriplegia, acquired microcephaly, and severe intellectual disability. General examination showed distal arthrogryposis predominant in the hands in both siblings and severe left dorso-lumbar convex scoliosis in one. WGS of the siblings-parents quartet identified novel compound heterozygous mutations in SLC35A3 in both children. SLC35A3 encodes the major Golgi uridine diphosphate N-acetylglucosamine transporter. With this study, we add SLC35A3 to the gene list of epilepsies. Neurological symptoms and skeletal abnormalities might result from impaired glycosylation of proteins involved in normal development and function of the central nervous system and skeletal apparatus.


Assuntos
Artrogripose/genética , Deficiência Intelectual/genética , Microcefalia/genética , Mutação , Proteínas de Transporte de Nucleotídeos/genética , Quadriplegia/genética , Espasmos Infantis/genética , Artrogripose/diagnóstico , Artrogripose/patologia , Osso e Ossos/anormalidades , Criança , Eletroencefalografia , Feminino , Expressão Gênica , Glicosilação , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Masculino , Microcefalia/diagnóstico , Microcefalia/patologia , Quadriplegia/diagnóstico , Quadriplegia/patologia , Irmãos , Espasmos Infantis/diagnóstico , Espasmos Infantis/patologia
17.
Am J Hum Genet ; 100(4): 659-665, 2017 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-28318499

RESUMO

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.


Assuntos
Artrogripose/genética , Proteínas da Matriz Extracelular/genética , Mutação , Células de Schwann/metabolismo , Artrogripose/diagnóstico , Artrogripose/patologia , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Bainha de Mielina/metabolismo , Linhagem
18.
PLoS Negl Trop Dis ; 11(2): e0005363, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28231241

RESUMO

The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans) produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc) embryos. Exposure to the virus at 7.5-9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR), rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities correlated with damage to the placenta, particularly to the labyrinthine layer, suggesting that circulatory changes are integral to the altered phenotypes.


Assuntos
Artrogripose/virologia , Modelos Animais de Doenças , Hidrocefalia/virologia , Complicações Infecciosas na Gravidez/virologia , Infecção por Zika virus/virologia , Zika virus/fisiologia , Animais , Artrogripose/embriologia , Artrogripose/imunologia , Artrogripose/patologia , Feminino , Humanos , Hidrocefalia/embriologia , Hidrocefalia/imunologia , Hidrocefalia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Placenta/anormalidades , Placenta/imunologia , Placenta/virologia , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/patologia , Teratogênios/análise , Infecção por Zika virus/embriologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/patologia
19.
J Pediatr Endocrinol Metab ; 30(3): 361-364, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28222034

RESUMO

BACKGROUND: Gordon syndrome (GS) is a rare form of monogenic hypertension characterized by low renin hypertension, hyperkalemia, hyperchloremic metabolic acidosis, and normal glomerular filtration rate. To date, four genes causing GS have been identified as: WNK1, WNK4, CUL3, and KLHL3. CASE PRESENTATION: We report three cases of GS in two families. All patients presented with typical clinical features of GS and had a known dominant KLHL3 mutation. Oral thiazide treatment with low salt diet resulted in normalization of blood pressure and serum electrolytes in all three cases. CONCLUSIONS: GS should be considered in patients with low renin hypertension and hyperkalemia. Although it is a rare disease, the correct diagnosis of GS is clinically important, as it can easily be treated with a low sodium diet or thiazides. In addition, family studies can identify individuals with undiagnosed GS as all mutations causing this disease, except for some recessive KLHL3 mutations, are dominant mutations.


Assuntos
Artrogripose/genética , Artrogripose/patologia , Biomarcadores/metabolismo , Proteínas de Transporte/genética , Fissura Palatina/genética , Fissura Palatina/patologia , Pé Torto Equinovaro/genética , Pé Torto Equinovaro/patologia , Genes Dominantes/genética , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Mutação/genética , Adulto , Pré-Escolar , Feminino , Humanos , Lactente , Fenótipo , Prognóstico
20.
J Hepatol ; 66(5): 1001-1011, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28082148

RESUMO

BACKGROUND & AIMS: In the normal liver, hepatocytes form a uniquely polarised cell layer that enables movement of solutes from sinusoidal blood to canalicular bile. Whilst several cholestatic liver diseases with defects of hepatocyte polarity have been identified, the molecular mechanisms of pathogenesis are not well defined. One example is arthrogryposis, renal dysfunction and cholestasis syndrome, which in most patients is caused by VPS33B mutations. VPS33B is a protein involved in membrane trafficking that interacts with RAB11A at recycling endosomes. To understand the pathways that regulate hepatocyte polarity better, we investigated VPS33B deficiency using a novel mouse model with a liver-specific Vps33b deletion. METHODS: To assess functional polarity, plasma and bile samples were collected from Vps33b liver knockout (Vps33bfl/fl-AlfpCre) and control (Vps33bfl/fl) mice; bile components or injected substrates were quantitated by mass spectrometry or fluorometry. For structural analysis, livers underwent light and transmission electron microscopy. Apical membrane and tight junction protein localisation was assessed by immunostaining. Adeno-associated virus vectors were used for in vivo gene rescue experiments. RESULTS: Like patients, Vps33bfl/fl-AlfpCre mice showed mislocalisation of ATP-binding cassette proteins that are specifically trafficked to the apical membrane via Rab11a-positive recycling endosomes. This was associated with retention of bile components in blood. Loss of functional tight junction integrity and depletion of apical microvilli were seen in knockout animals. Gene transfer partially rescued these defects. CONCLUSIONS: Vps33b has a key role in establishing structural and functional aspects of hepatocyte polarity and may be a target for gene replacement therapy. LAY SUMMARY: Hepatocytes are liver cells with tops and bottoms; that is, they are polarised. At their bottoms they absorb substances from blood. They then, at their tops, secrete these substances and their metabolites into bile. When polarity is lost, this directional flow of substances from blood to bile is disrupted and liver disease follows. In this study, using a new mouse model with a liver-specific mutation of Vps33b, the mouse version of a gene that is mutated in most patients with arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, we investigated how the Vps33b gene product contributes to establishing hepatocyte polarity. We identified in these mice abnormalities similar to those in children with ARC syndrome. Gene transfer could partly reverse the mouse abnormalities. Our work contributes to the understanding of VPS33B disease and hepatocyte polarity in general, and may point towards gene transfer mediated treatment of ARC liver disease.


Assuntos
Polaridade Celular , Hepatócitos/fisiologia , Proteínas de Transporte Vesicular/fisiologia , Animais , Artrogripose/patologia , Artrogripose/terapia , Ácidos e Sais Biliares/sangue , Colestase/patologia , Colestase/terapia , Colesterol/sangue , Terapia Genética , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Insuficiência Renal/patologia , Insuficiência Renal/terapia , Junções Íntimas/fisiologia , Proteínas de Transporte Vesicular/genética
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