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1.
Am J Med Genet A ; 191(9): 2428-2432, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37462082

RESUMO

Mitogen-activated protein kinase 8-interacting protein 3 gene (MAPK8IP3) encodes the c-Jun-amino-terminal kinase-interacting protein 3 (JIP3) and is involved in retrograde axonal transport. Heterozygous de novo pathogenic variants in MAPK8IP3 result in a neurodevelopmental disorder with or without brain abnormalities and possible axonal peripheral neuropathy. Whole-exome sequencing was performed on an individual presenting with severe congenital muscle hypotonia of neuronal origin mimicking lethal spinal muscular atrophy. Compound heterozygous rare variants (a splice and a missense) were detected in MAPK8IP3, inherited from the healthy parents. Western blot analysis in a muscle biopsy sample showed a more than 60% decrease in JIP3 expression. Here, we suggest a novel autosomal recessive phenotype of a lower motor neuron disease caused by JIP3 deficiency.


Assuntos
Atrofia Muscular Espinal , Doenças Musculares , Anormalidades Musculoesqueléticas , Humanos , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patologia , Fenótipo , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas Adaptadoras de Transdução de Sinal/genética
2.
Orv Hetil ; 147(15): 697-702, 2006 Apr 16.
Artigo em Húngaro | MEDLINE | ID: mdl-16734182

RESUMO

Transcription factors are highly conserved proteins with preserved structure and function for up to a hundred million years. They regulate protein formation and function by binding to DNA and controlling gene expression. Mutations are generally lethal, but can play role in endocrine disorders and tumor genesis. They are necessary for cell growth, proliferation, differentiation and are required in tissue and organ development during normal embryogenesis. Consequently, transcription factors are essential in developmental processes and homeostasis. Mutations of genes encoding transcriptional regulators have been shown to be involved in a number of various genetic diseases, in particular malformation of the skeletal system, cranium, limbs, as well as some congenital syndromes with anomalies of these organs and somatic/mental retardation. Evidences accumulate to support the need of transcription factor mutation identification in the clinical practice. The present study reviews the most important congenital malformations and genetic syndromes which are thought to be related to mutations in classic transcription factors, and in which determination of transcription factors might be of clinical significance, even in the near future, for exact causative diagnosis and genetic counseling in affected families. In addition, studies of the transcription factors may lead to a better understanding of human embryogenesis.


Assuntos
Anormalidades Congênitas/genética , Genes Homeobox , Mutação , Fatores de Transcrição/genética , Doenças do Desenvolvimento Ósseo/genética , Proteínas de Ligação a DNA/genética , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Homeodomínio/genética , Humanos , Deficiência Intelectual/genética , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição SOXB1 , Proteína de Homoeobox de Baixa Estatura , Proteínas com Domínio T/genética
3.
Clin Dysmorphol ; 15(1): 29-31, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16317304

RESUMO

Wiedemann-Rautenstrauch syndrome is a rare disorder with a progressive course and early lethality. Severe mental and growth retardation, muscle hypotonia, a progeroid face, wrinkled skin, relative macrocephaly with late closure of the anterior fontanel, arachnodactyly and congenital heart defects are also typical. We report on a female infant with all the characteristic features of this syndrome after birth. Chromosomal studies on peripheral leukocytes showed a normal karyotype. In view of an abnormal lipid distribution and lipodystrophy, metabolic studies for congenital disorders of glycosylation have been performed with normal results. At the age of 2 years 6 months the progeroid signs were no longer present, and the patient had a striking improvement in her psychomotor development. As there are overlapping features in Wiedemann-Rautenstrauch syndrome and in mosaic polyploidy, including psychomotor retardation, reduced peripheral muscle bulk, arachnodactyly and lipodystrophy, chromosome analysis was performed in the fibroblast culture of our patient. A mosaic triploidy/tetraploidy was detected in 60% and 14% of the cells, respectively. We therefore recommend chromosome analysis of fibroblasts from patients with a neonatal presentation of progeroid features and lipodystrophy.


Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Lipodistrofia/genética , Poliploidia , Progéria/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Pré-Escolar , Transtornos Cromossômicos/patologia , Feminino , Humanos , Recém-Nascido , Lipodistrofia/patologia , Fenótipo , Progéria/patologia
4.
Clin Dysmorphol ; 12(3): 161-5, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-14564152

RESUMO

The ulnar-mammary syndrome (MIM 181450) includes postaxial ray defects, abnormalities of growth, delayed sexual development, and mammary and apocrine gland hypoplasia. Brachydactyly type E (MIM 113300) presents with shortening of the metacarpals and phalanges in the ulnar ray in association with moderately short stature. We describe a three-generation family with variable expression of ulnar/fibular hypoplasia, brachydactyly, ulnar ray defects and short stature. The proband had ulnar hypoplasia with missing IV-Vth fingers, fibular hypoplasia on the right, bilateral club feet, growth retardation, a hypoplastic mid-face, an ASD and hemangiomas. She had normal mammary tissue and normal sweating. The mother had short stature, midfacial hypoplasia, a hypoplastic ulna and hypoplasia of the IVth metacarpal (brachydactyly) on the right without other associated malformations. The maternal grandfather had mild bilateral fibular hypoplasia and midphalangeal brachydactyly of the IV-Vth toes. His sister had mild short stature and shortening of the IVth metacarpal of the left hand. Two-point linkage analysis with microsatellite markers spanning the Ulnar-Mammary locus at 12q24.1 did not confirm linkage. The patients may have a previously undescribed syndrome.


Assuntos
Genes Dominantes , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Ulna/anormalidades , Adulto , Estatura , Saúde da Família , Feminino , Dedos/anormalidades , Humanos , Lactente , Masculino , Metacarpo/anormalidades , Linhagem
5.
Am J Med Genet A ; 116A(3): 272-7, 2003 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-12503106

RESUMO

Frontometaphyseal dysplasia is a rare genetic syndrome affecting the skeletal system and connective tissue. It is believed to be inherited as an X-linked trait. Features of frontometaphyseal dysplasia overlap with other skeletal dysplasias. Prominent supraorbital ridges, radiologic evidence of cranial hyperostosis, and flared metaphyses are characteristic. Scoliosis, a rare associated finding, is usually mild, and familial progressive scoliosis has not been reported so far. The skeletal dysplasia and the associated clinical findings show significant intra- and interfamilial variability. The syndrome has been suggested to be an allelic variant of the Melnick-Needles osteodysplasty, an X-linked (dominant) entity. We present two families with frontometaphyseal dysplasia, in which both males and females showed the facial and skeletal features of the syndrome in association with progressive scoliosis. Some of the affected members also had hearing loss and urogenital anomalies, supporting the existence of the recently suggested entity "fronto-otopalatodigital-osteodysplasty syndome".


Assuntos
Anormalidades Múltiplas/patologia , Doenças do Desenvolvimento Ósseo/patologia , Osso Frontal/anormalidades , Escoliose/patologia , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Saúde da Família , Feminino , Heterogeneidade Genética , Humanos , Masculino , Linhagem , Radiografia , Escoliose/diagnóstico por imagem , Escoliose/genética
6.
Eur J Pediatr ; 161(11): 619-22, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12424590

RESUMO

UNLABELLED: Cleidocranial dysplasia (CCD; MIM 119600) is an autosomal dominant skeletal dysplasia characterised by hypoplastic clavicles, patent fontanelles, short stature, tooth anomalies and other variable skeletal changes. Different mutations of the RUNX2/CBFA1 gene (MIM 600211) have been detected in patients with CCD. We investigated a mother and daughter with features of CCD presenting with reduced plasma alkaline phosphatase activity, increased urinary phosphoethanolamine excretion and decreased bone density. The latter findings were suggestive of hypophophatasia but mutation analysis showed no mutation in the tissue-nonspecific alkaline phosphatase gene (TNSALP; MIM 171760). However, a heterozygous mutation (Arg169Pro caused by nucleotide change 506G > C) was detected in the RUNX2 gene. Metabolic alterations gradually improved in both mother and daughter but bone-specific alkaline phosphatase remained low (less than 30% of normal) and mild phosphoethanolaminuria persisted. Recent studies in the Cbfa1 knock-out mouse showed decreased expression of alkaline phosphatase in differentiating bone. CONCLUSION: we suggest that the observed metabolic alterations are secondary to the RUNX2 gene mutation affecting early bone maturation and turnover. This is the first description of biochemical findings of hypophosphatasia in patients with cleidocranial dysplasia.


Assuntos
Densidade Óssea , Displasia Cleidocraniana/enzimologia , Displasia Cleidocraniana/genética , Hipofosfatasia/complicações , Proteínas de Neoplasias , Fatores de Transcrição/genética , Fosfatase Alcalina/sangue , Criança , Displasia Cleidocraniana/etiologia , Displasia Cleidocraniana/fisiopatologia , Subunidade alfa 1 de Fator de Ligação ao Core , Análise Mutacional de DNA , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação
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