Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros








Base de dados
Intervalo de ano de publicação
2.
Clin Genet ; 106(3): 293-304, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38733153

RESUMO

Maturity-Onset Diabetes of the Young (MODY) is a diabetes mellitus subtype caused by a single gene. The detection rate of the responsible gene is 27% in the United Kingdom, indicating that the causative gene remains unknown in the majority of clinically diagnosed MODY cases. To improve the detection rate, we applied comprehensive genetic testing using whole exome sequencing (WES) followed by Multiplex Ligation-dependent Probe Amplification (MLPA) and functional analyses. Twenty-one unrelated Japanese participants with MODY were enrolled in the study. To detect copy number variations (CNVs), WES was performed first, followed by MLPA analysis for participants who were negative on the basis of WES. Undetermined variants were analyzed according to their functional properties. WES identified 7 pathogenic and 3 novel likely pathogenic variants in the 21 participants. Functional analyses revealed that 1 in 3 variants was pathogenic. MLPA analysis applied to the remaining 13 undetermined samples identified 4 cases with pathogenic CNVs: 3 in HNF4A and 1 in HNF1B. Pathogenic variants were identified in 12 participants (12/21, 57.1%) - relatively high rate reported to date. Notably, one-third of the participants had CNVs in HNF4A or HNF1B, indicating a limitation of WES-only screening.


Assuntos
Variações do Número de Cópias de DNA , Diabetes Mellitus Tipo 2 , Sequenciamento do Exoma , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiologia , População do Leste Asiático/genética , Predisposição Genética para Doença , Testes Genéticos , Fator 1-beta Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Japão/epidemiologia , Reação em Cadeia da Polimerase Multiplex , Mutação , Prevalência
3.
Endocr J ; 70(6): 629-634, 2023 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-37045781

RESUMO

Glucokinase is a glycolytic enzyme that catalyzes the phosphorylation of glucose to glucose-6-phospate in the first step of the glycolytic pathway. It also regulates the threshold for insulin secretion from pancreatic beta cells by catalyzing the phosphorylation of glucose and plays an important role as a glucose sensor. Pathogenic variants in the glucokinase gene (GCK) cause non-progressive but persistent mild fasting hyperglycemia, also recognized as maturity-onset diabetes of the young 2 (MODY2). This report presents the case of two Japanese siblings with MODY2, who were initially diagnosed with impaired glucose intolerance at 20 and 17 years of age, and later developed diabetes mellitus. They had no history of obesity, were negative for islet-related autoantibodies and their serum C-peptide level were within the normal range. Diabetic complications were not observed. Next-generation sequencing revealed a novel heterozygous variant in GCK (NM_000162.5: c.1088A>G, p.Asp363Gly) in both siblings. This variant has not been reported previously. In silico functional analyses, using SIFT and MutationTaster, suggested that the variant was damaging. To confirm the functional impact of the mutated GCK, the HiBiT-tagged p.Asp363Gly variant and the wild-type GCK were transiently expressed in HEK293T cells. The cells expressing the variant GCK exhibited 79% less bioluminescence, compared to those expressing the wild-type GCK, suggesting that the pathophysiology of the variant was a result of haploinsufficiency.


Assuntos
Diabetes Mellitus Tipo 2 , Glucoquinase , Humanos , Glucoquinase/genética , Glucoquinase/metabolismo , Mutação , População do Leste Asiático , Células HEK293 , Irmãos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/diagnóstico , Glucose
4.
Ann Clin Transl Neurol ; 7(10): 2047-2051, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32886413

RESUMO

Mutations in the lysine methyltransferase 2B (KMT2B) gene have recently been reported to be associated with childhood-onset generalized dystonia. There have been no studies investigating ablative treatments for the management of this disorder. Three patients underwent either a staged unilateral pallidotomy and contralateral pallidothalamic tractotomy (19-year-old man, 2-year follow-up), a unilateral pallidothalamic tractotomy (34-year-old man, 6-month follow-up) or a simultaneous unilateral pallidothalamic tractotomy and ventro-oral thalamotomy (29-year-old man, 6-month follow-up). The average total patient score on the Burke-Fahn-Marsden Dystonia Rating Scale-Movement Scale improved from 39.5 to 13.2 (66.6%) after the procedures. No significant complications were identified. Ablative treatments appear to be a promising alternative surgical option for generalized dystonia with KMT2B mutation.


Assuntos
Distonia/terapia , Adolescente , Adulto , Criança , Estimulação Encefálica Profunda/métodos , Distonia/genética , Distúrbios Distônicos/genética , Distúrbios Distônicos/prevenção & controle , Seguimentos , Humanos , Masculino , Mutação/genética , Palidotomia/métodos , Ablação por Radiofrequência/instrumentação , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA