MedElevator
Войти в исследования Molecular genetics & genomic medicine · 2020
Identification of a missense ARSA mutation in metachromatic leukodystrophy and its potential pathogenic mechanism.
Клинический случайСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Guo Liyuan, Jin Bo, Zhang Yidan, Wang Jing
Аннотация
BACKGROUND: Metachromatic leukodystrophy (MLD) is a rare inherited lysosomal disorder caused by mutations in ARSA. The biological processes of MLD disease caused by candidate pathogenic mutations in the ARSA gene remain unclear.
METHODS: We used whole-exome sequencing (WES) and Sanger sequencing to identify the pathogenic mutation in a Chinese family. Literature review and protein three-dimensional structure prediction were performed to analyze the potential pathogenesis of the identified mutations. Overexpression cell models of wild-type and mutated ARSA genes were constructed. The accumulated sulfatides and expression profiles in the cell models were detected, and a series of bioinformatics analyses were carried out to compare the biological changes caused by the candidate pathogenic mutations.
RESULTS: We identified an ARSA c.925G>A homozygous mutation from a Chinese late-infantile MLD patient, the first report of this mutation in East Asia. The literature and protein structure analysis indicated that three types of mutations at c.925G (c.925G>A, c.925G>T, c.925G>C) were pathogenic. The overexpression of wild-type or mutated ARSA genes influenced the accumulation of sulfatides. The co-expression modules in the mutated cell models were constructed by genes related to calcium signaling and vesicle transport.
CONCLUSION: Our results identified a pathogenic mutation, ARSA homozygosity c.925G>A, from a Chinese MLD family. The pathogenic mechanism of the ARSA mutation in MLD was identified, which may suggest new approaches to diagnosis and treatment.
METHODS: We used whole-exome sequencing (WES) and Sanger sequencing to identify the pathogenic mutation in a Chinese family. Literature review and protein three-dimensional structure prediction were performed to analyze the potential pathogenesis of the identified mutations. Overexpression cell models of wild-type and mutated ARSA genes were constructed. The accumulated sulfatides and expression profiles in the cell models were detected, and a series of bioinformatics analyses were carried out to compare the biological changes caused by the candidate pathogenic mutations.
RESULTS: We identified an ARSA c.925G>A homozygous mutation from a Chinese late-infantile MLD patient, the first report of this mutation in East Asia. The literature and protein structure analysis indicated that three types of mutations at c.925G (c.925G>A, c.925G>T, c.925G>C) were pathogenic. The overexpression of wild-type or mutated ARSA genes influenced the accumulation of sulfatides. The co-expression modules in the mutated cell models were constructed by genes related to calcium signaling and vesicle transport.
CONCLUSION: Our results identified a pathogenic mutation, ARSA homozygosity c.925G>A, from a Chinese MLD family. The pathogenic mechanism of the ARSA mutation in MLD was identified, which may suggest new approaches to diagnosis and treatment.