Identification of a Novel Hemizygous SQSTM1 Nonsense Mutation in Atypical Behavioral Variant Frontotemporal Dementia

Frontiers in Aging Neuroscience
Lin SunXia Li

Abstract

Frontotemporal dementia includes a large spectrum of neurodegenerative disorders.SQSTM1, coding for p62 protein, plays a vital role in the pathogenesis of FTD. Here, we report a case of a female patient withSQSTM1mutation S224X, who was 59 years old when she initially exhibited memory decline, mild personality changes, and subtle atrophy of frontal/temporal lobes in magnetic resonance imaging (MRI). Genetic testing revealed a nonsense mutation of theSQSTM1gene (S224X), resulting in premature termination of protein synthesis and a predicted truncated protein 217 amino acids shorter than the normal protein. Moreover, neither intact nor truncated SQSTM1 proteins was detectable inSQSTM1S224X mutant overexpressing HEK-293T cells. We assayed forSQSTM1cDNA in samples from the patient's peripheral leucocytes, and did not detect its mutation. The test of quantitative PCR showed significant decreased level ofSQSTM1mRNA from peripheral leucocytes of the patient compared to five dementia controls. Our results identify a novel pathogenicSQSTM1S224X mutation in an atypical FTD patient accompanied with loss of SQSTM1/p62 protein expression probably due toSQSTM1gene haploinsufficiency.

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Citations

Dec 17, 2020·Journal of Alzheimer's Disease : JAD·Tiziana CarandiniDaniela Galimberti
Sep 6, 2020·Neurobiology of Disease·Suvi HäkkinenSuzee E Lee

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Methods Mentioned

BETA
electrophoresis
exome sequencing
genotyping
Transfection
PCR

Software Mentioned

Mutation
PyroMark
Taster
Mutation Taster

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