scholarly journals Clinical and Molecular Spectrum of Glutamate Dehydrogenase Gene Defects in 26 Chinese Congenital Hyperinsulinemia Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Chang Su ◽  
Xue-Jun Liang ◽  
Wen-Jing Li ◽  
Di Wu ◽  
Min Liu ◽  
...  
Keyword(s):  
Glutamate Dehydrogenase ◽  
De Novo ◽  
Mutational Analysis ◽  
Age At Onset ◽  
Normal Serum ◽  
Protein Restriction ◽  
Chinese Patients ◽  
Congenital Hyperinsulinism ◽  
Missense Mutations ◽  
De Novo Mutations

Objective. To characterize the genotype and phenotype of Chinese patients with congenital hyperinsulinism (CHI) caused by activating mutations in GLUD1, the gene that encodes mitochondrial enzyme glutamate dehydrogenase (GDH). Methods. The clinical data of glutamate dehydrogenase hyperinsulinism (GDH-HI) patients were reviewed, and gene mutations were confirmed by whole exome sequencing (WES) and Sanger DNA sequencing. Results. Twenty-six patients with GDH-HI heterozygous missense mutations were identified from 240 patients diagnosed as congenital hyperinsulinism over past 15 years. The median age at onset was 8 months (range: 1 day of life to 3 years). Seizure disorder was common in our cohort of patients (23/26). Four patients had normal serum ammonia levels; the median serum concentration was 101 μmol/L (range: 37–190 μmol/L). Hypoglycemic symptoms could be triggered by fasting or protein meals in all patients while blood glucose could be well controlled in all patients with diazoxide. Dosage of diazoxide could be reduced by protein restriction. Attempts to lower ammonia levels failed with different therapies such as protein restriction, benzoate, or N-carbamoyl glutamate. In follow-up, 15 of 26 patients had normal intelligence. Eleven patients developed epilepsy at the age of 6 months to 11 years. De novo mutations in GLUD1 were found in 24 cases, and dominant inheritance was observed in the other two; all were heterozygous. A total of 35% (9/26) patients carried c.1493C>T (p.S445L) mutation. Conclusions. Phenotypic heterogeneity of GDH-HI patients was observed within the Chinese cohort in the present study. The fact that most patients had a GLUD1 p. S445L mutation implies that this site could be a hotspot in Chinese patients. A high frequency of GDH-HI with normal ammonia has been reported in this study. Hence, GLUD1 mutational analysis may be an important method to differential diagnosis of GDH-HI from other diazoxide-responsive CHI in Chinese patients.

Multimodal Imaging and Genetic Characteristics of Chinese Patients with USH2A-Associated Nonsyndromic Retinitis Pigmentosa

2020 ◽  
Author(s):  
Chong Chen ◽  
Qiao Sun ◽  
Mingmin Gu ◽  
Tianwei Qian ◽  
Dawei Luo ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
De Novo ◽  
Molecular Genetic ◽  
In Silico Analysis ◽  
Chinese Patients ◽  
Insertion Mutation ◽  
Missense Mutations ◽  
De Novo Mutations ◽  
Cross Sectional ◽  
Genetic Characteristics

Abstract Background To determine the clinical characteristics and molecular genetic background responsible for USH2A mutations associated with nonsyndromic retinitis pigmentosa (RP) in five Chinese families, a retrospective cross-sectional study was performed. Data of detailed history and comprehensive ophthalmological examinations were extracted from medical charts. Genomic DNA was sequenced by whole-exome sequencing. The pathogenicity predictions were evaluated by in silico analysis. The structural modeling of the wide-type and mutant USH2A proteins was displayed based on I-Tasser software.Results The ultrawide-field fundus imaging showed a distinctive pattern of hyperautofluorescence in the parafoveal ring with macular sparing. Ten USH2A variants were detected, including seven missense mutations, two splicing mutations and one insertion mutation. Six of these variants have already been reported, and the remaining four were novel. Of the de novo mutations, the p.C931Y and p.G4489S mutations were predicted to be deleterious or probably damaging; the p.M4853V mutation was predicted to be neutral or benign; and the IVS22+3A>G mutation was a splicing mutation that could influence mRNA splicing and affect the formation of the hairpin structure of the USH2A protein.Conclusions Our data further confirm that USH2A plays a pivotal role in the maintenance of photoreceptors and expand the spectrum of USH2A mutations that are associated with nonsyndromic RP in Chinese patients.

Identification of two de novo mutations in Chinese patients with X-linked adrenoleukodystrophy

2008 ◽  
Vol 46 (12) ◽  
Author(s):  
Zhihong Wang ◽  
Longfeng Ke ◽  
Aizhen Yan ◽  
Zhongyong Zhu ◽  
Fenghua Lan
Keyword(s):  
De Novo ◽  
Chinese Patients ◽  
De Novo Mutations

scholarly journals A SMARCA2 Mutation in the First Case Report of Nicolaides-Baraitser Syndrome in Latin America: Genotype-Phenotype Correlation

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Ana Isabel Sánchez ◽  
Jorge Armando Rojas
Keyword(s):  
Latin America ◽  
Case Report ◽  
Language Impairment ◽  
De Novo ◽  
Signs And Symptoms ◽  
Facial Features ◽  
Missense Mutations ◽  
De Novo Mutations ◽  
Lower Lip ◽  
First Case

Nicolaides-Baraitser syndrome (NCBRS) is a rare and well-recognized entity that was first described in 1993, with a prevalence that is currently not known. It is recognized as a distinctive entity, with some variability in its signs and symptoms. The most important characteristics include intellectual disability, peculiar facial features including sparse scalp hair, coarse facial features, low frontal hairline, and microcephaly, and seizures. Additional features may include epicanthic folds, thin upper lip vermilion with thick lower lip vermilion, skeletal abnormalities, and severe language impairment. The disorder is inherited in an autosomal dominant manner caused by de novo mutations in the SMARCA2 gene, with most being missense mutations. We report a young adult patient with NCBRS and, to our knowledge, the first case report of the syndrome in Latin America with a confirmed molecular diagnosis and a mild-to-moderate phenotype.

Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome

2001 ◽  
Vol 108 (1) ◽  
pp. 66-71 ◽  
Author(s):  
Ren� Santer ◽  
Martina Kinner ◽  
Andrea Superti-Furga ◽  
Reinhard Schneppenheim ◽  
Ertan Mayatepek ◽  
...  
Keyword(s):  
Glutamate Dehydrogenase ◽  
Congenital Hyperinsulinism ◽  
Missense Mutations

scholarly journals A de novo paradigm for male infertility

2021 ◽  
Author(s):  
MS Oud ◽  
RM Smits ◽  
HE Smith ◽  
FK Mastrorosa ◽  
GS Holt ◽  
...  
Keyword(s):  
Male Infertility ◽  
De Novo ◽  
P Value ◽  
Missense Mutations ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Systematic Analysis ◽  
Significant Enrichment

IntroductionDe novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness1. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. To test this hypothesis, we performed trio-based exome-sequencing in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00×10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01×10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing2. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.

Novel missense mutations in the glutamate dehydrogenase gene in the congenital hyperinsulinism-hyperammonemia syndrome

2000 ◽  
Vol 136 (1) ◽  
pp. 69-72 ◽  
Author(s):  
Yuko Miki ◽  
Tomohiko Taki ◽  
Toshihiro Ohura ◽  
Hitoshi Kato ◽  
Masayoshi Yanagisawa ◽  
...  
Keyword(s):  
Glutamate Dehydrogenase ◽  
Congenital Hyperinsulinism ◽  
Missense Mutations ◽  
Dehydrogenase Gene

A novel mutation in the glutamate dehydrogenase (GLUD1) of a patient with congenital hyperinsulinism-hyperammonemia (HI/HA)

2016 ◽  
Vol 29 (3) ◽  
Author(s):  
Chen Fang ◽  
Xin Ding ◽  
Yun Huang ◽  
Jian Huang ◽  
Pengjun Zhao ◽  
...  
Keyword(s):  
Birth Weight ◽  
Missense Mutation ◽  
Glutamate Dehydrogenase ◽  
De Novo ◽  
Novel Mutation ◽  
Genetic Diagnosis ◽  
Congenital Hyperinsulinism ◽  
Normal Birth Weight ◽  
Normal Birth

AbstractHyperinsulinism-hyperammonemia (HI/HA) syndrome, often characterized by recurrent symptomatic hypoglycemia and persistent hyperammonemia, is the second most frequent cause of the congenital hyperinsulinism (CHI). Here, we reported a patient with normal birth weight, repeated seizures, untreatable hypoglycemia, and persistent, mild hyperammonemia. The genetic diagnosis revealed that the patient carried a heterozygous, de novo missense mutation (N410I, c.1401A>T) in the glutamate dehydrogenase 1 gene (

scholarly journals Hyperinsulinism–hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype–phenotype correlations

2009 ◽  
Vol 161 (5) ◽  
pp. 731-735 ◽  
Author(s):  
Ritika R Kapoor ◽  
Sarah E Flanagan ◽  
Piers Fulton ◽  
Anupam Chakrapani ◽  
Bernadette Chadefaux ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Mutational Analysis ◽  
Novel Mutation ◽  
Ammonia Concentration ◽  
Normal Serum ◽  
Missense Mutations ◽  
Mitochondrial Enzyme ◽  
Activating Mutations ◽  
Gene Functional Analysis ◽  
Serum Ammonia

BackgroundActivating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism–hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion.ObjectivesTo study the genotype–phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA.Patients and methodsTwenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed.ResultsHeterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 μmol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified.ConclusionPatients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations.

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