Dataset Information

Identification of a novel mutation in APP gene in a Thai subject with early-onset Alzheimer's disease.

ABSTRACT: Introduction:Early-onset Alzheimer's disease (AD) accounts for than less 1% of all AD cases, with large variation in the reported genetic contributions of known dementia genes. Mutations in the amyloid precursor protein (APP) gene were the first to be recognized as the cause of AD. Methods:Here, a male patient with probable early-onset AD at the age of 55 years from Thailand was investigated by next-generation sequencing. Results:A novel mutation in exon 14 of APP (c.1810C>T, p.V604M) was found. He initially illustrated the clinical manifestations of progressive nonfluent aphasia in 2011. However, he was finally diagnosed with AD presenting logopenic aphasia in 2013. The follow-up magnetic resonance imaging scan showed progression of hippocampal trophy compared with the initial image. A 3D protein structure model revealed that V604M exchange could result in significant changes in the APP protein due to the increased hydrophobicity of methionine in the helix, which could result in altering of the APP functions. Conclusion:Additional studies to characterize APP p.V604M are necessary to further understand the effects of this mutation.

SUBMITTER: Van Giau V

PROVIDER: S-EPMC6231518 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Identification of a novel mutation in <i>APP</i> gene in a Thai subject with early-onset Alzheimer's disease.

Van Giau Vo V Senanarong Vorapun V Bagyinszky Eva E Limwongse Chanin C An Seong Soo A SSA Kim SangYun S

Neuropsychiatric disease and treatment 20181108

<h4>Introduction</h4>Early-onset Alzheimer's disease (AD) accounts for than less 1% of all AD cases, with large variation in the reported genetic contributions of known dementia genes. Mutations in the amyloid precursor protein (<i>APP</i>) gene were the first to be recognized as the cause of AD.<h4>Methods</h4>Here, a male patient with probable early-onset AD at the age of 55 years from Thailand was investigated by next-generation sequencing.<h4>Results</h4>A novel mutation in exon 14 of <i>APP ...[more]

PMID: 30510423

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Project description:BackgroundSandhoff disease (SD) is an autosomal recessive lysosomal storage disorder, resulting in accumulation of GM2 ganglioside, particular in neuronal cells. The disorder is caused by deficiency of β-hexosaminidase B (HEX-B), due to pathogenic variant of human HEXB gene.MethodThis study describes clinical features, biochemical, and genetic defects among Thai patients with infantile SD during 2008-2019.ResultsFive unrelated Thai patients presenting with developmental regression, axial hypotonia, seizures, exaggerated startle response to noise, and macular cherry red spot were confirmed to have infantile SD based on deficient HEX enzyme activities and biallelic variants of the HEXB gene. In addition, an uncommon presenting feature, cardiac defect, was observed in one patient. All the patients died in their early childhood. Plasma total HEX and HEX-B activities were severely deficient. Sequencing analysis of HEXB gene identified two variants including c.1652G>A (p.Cys551Tyr) and a novel variant of c.761T>C (p.Leu254Ser), in 90 and 10% of the mutant alleles found, respectively. The results from in silico analysis using multiple bioinformatics tools were in agreement that the p.Cys551Tyr and the p.Leu254Ser are likely pathogenic variants. Molecular modelling suggested that the Cys551Tyr disrupt disulfide bond, leading to protein destabilization while the Leu254Ser resulted in change of secondary structure from helix to coil and disturbing conformation of the active site of the enzyme. Genome-wide SNP array analysis showed no significant relatedness between the five affected individuals. These two variants were not present in control individuals. The prevalence of infantile SD in Thai population is estimated 1 in 1,458,521 and carrier frequency at 1 in 604.ConclusionThe study suggests that SD likely represents the most common subtype of rare infantile GM2 gangliosidosis identified among Thai patients. We firstly described a potential common variant in HEXB in Thai patients with infantile onset SD. The data can aid a rapid molecular confirmation of infantile SD starting with the hotspot variant and the use of expanded carrier testing.

Dataset Information

Identification of a novel mutation in APP gene in a Thai subject with early-onset Alzheimer's disease.

Publications

Identification of a novel mutation in <i>APP</i> gene in a Thai subject with early-onset Alzheimer's disease.

Similar Datasets

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