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 with SQSTM1 mutation 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 the SQSTM1 gene (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 in SQSTM1 S224X mutant overexpressing HEK-293T cells. We assayed for SQSTM1 cDNA in samples from the patient's peripheral leucocytes, and did not detect its mutation. The test of quantitative PCR showed significant decreased level of SQSTM1 mRNA from peripheral leucocytes of the patient compared to five dementia controls. Our results identify a novel pathogenic SQSTM1 S224X mutation in an atypical FTD patient accompanied with loss of SQSTM1/p62 protein expression probably due to SQSTM1 gene haploinsufficiency.
Highlights
Frontotemporal dementia is the second common form of neurodegenerative dementia in presenile population, characterized by atrophy of frontal and/or temporal lobes, and is frequently linked to genetic mutations (Miller et al, 2015; Luis et al, 2016)
The patient exhibited early-onset dementia combined with the initial symptom of memory decline, a gradual appearance of mild personality change, subtle atrophy of frontal/temporal lobes in magnetic resonance imaging (MRI), negative appearance in electromyogram/ nerve conduction velocity (EMG/NCV), and rapidly progressive course
Western blot of SQSTM1 recognized by Gly 410 and Gly 162 antibodies showed significant decrease of fully intact protein and truncated protein of SQSTM1
Summary
Frontotemporal dementia is the second common form of neurodegenerative dementia in presenile population, characterized by atrophy of frontal and/or temporal lobes, and is frequently linked to genetic mutations (Miller et al, 2015; Luis et al, 2016). The definite diagnosis is based on three major pathological subtypes characterized by the presence of 43 kDa TAR DNA-binding protein (TDP43), tau, or fused in sarcoma (FUS) positive neuronal inclusions (Boutoleau-Bretonniere et al, 2015). Mutations in the genes that encode microtubule associated protein tau (MAPT), progranulin and C9orf are the most common causes of FTD (Sun et al, 2017). SQSTM1, which has been identified in FTD in 2012 (Rubino et al, 2012), suggesting a role in the pathogenesis of neurodegenerative disease (Boutoleau-Bretonniere et al, 2015), is initially considered as a monogenic cause of Paget disease of bone (PDB) in 2002 (Laurin et al, 2002) and amyotrophic lateral sclerosis in 2011 (Fecto et al, 2011). Rubino et al only identified 3 missense mutations in the SQSTM1 gene in 3 of 170 Italian patients with FTD, and 3 missense variants in 3 of 124 Italian patients with ALS (Rubino et al, 2012)
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