SQSTM1Mutations in French Patients With Frontotemporal Dementia or Frontotemporal Dementia With Amyotrophic Lateral Sclerosis

Abstract

IMPORTANCE Mutations in the SQSTM1 gene, coding for p62, are a cause of Paget disease of bone and amyotrophic lateral sclerosis (ALS). Recently, SQSTM1 mutations were confirmed in ALS, and mutations were also identified in 3 patients with frontotemporal dementia (FTD), suggesting a role for SQSTM1 in FTD. OBJECTIVE To evaluate the exact contribution of SQSTM1 to FTD and FTD with ALS (FTD-ALS) in an independent cohort of patients. DESIGN A SQSTM1 mutation was first identified in a multiplex family with FTD by use of whole-exome sequencing. To evaluate the frequency of SQSTM1 mutations, we sequenced this gene in a cohort of patients with FTD or FTD-ALS, with no mutations in known FTD and ALS genes. SETTING Primary care or referral center. PARTICIPANTS An overall cohort of 188 French patients, including 132 probands with FTD and 56 probands with FTD-ALS. MAIN OUTCOMES AND MEASURES Frequency of SQSTM1 mutations in patients with FTD or FTD-ALS; description of associated phenotypes. RESULTS We identified 4 heterozygous missense mutations in 4 unrelated families with FTD; only 1 family had clinical symptoms of Paget disease of bone, and only 1 family had clinical symptoms of FTD-ALS, possibly owing to the low penetrance of some of the clinical manifestations. CONCLUSIONS AND RELEVANCE Although the frequency of the mutations is low in our series (4 of 188 patients [2%]), our results, similar to those already reported, support a direct pathogenic role of p62 in different types of FTD.

Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis

“…From the 6 rare variant we found, 4 (Table 1) had been previously reported in patients with ALS (Abramzon et al., 2012, Rubino et al., 2012). Among them, the SQSTM1 p.P392L is also known to be the most frequent SQSTM1 mutation in PDB (Laurin et al., 2002) and has also been reported in cases with FTD (Le Ber et al., 2013) and normal tension glaucoma (Scheetz et al., 2016), whereas VCP p.I27V and p.R159C have also been found in patients with IBMPFD (Chan et al., 2012, Rohrer et al., 2011), and the VCP p.I27V has also been recently reported in one sIBM patient (Weihl et al., 2015). The SQSTM1 p.A117V was reported in one early-onset AD patient (Cuyvers et al., 2015).…”

“…A recent study reported a splice donor variant in SQSTM1 in a family with an autosomal dominant distal myopathy and also in an unrelated patient with sporadic distal myopathy (Bucelli et al., 2015). In addition, mutations in SQSTM1 are well known to be associated with familial and/or sporadic Paget disease of bone, ALS, and frontotemporal dementia (FTD) (Fecto et al., 2011, Kwok et al., 2014, Laurin et al., 2002, Le Ber et al., 2013, Miller et al., 2015, Rubino et al., 2012). Mutations in valosin-containing protein ( VCP ) gene are known to cause an inherited form of IBM with Paget disease and frontotemporal dementia (IBMPFD) (Gidaro et al., 2008, Watts et al., 2004) and have also been reported in cases with ALS and FTD (Johnson et al., 2010, Koppers et al., 2012).…”

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

“…1b) bvFTD behavioral variant frontotemporal dementia, MND motor neuron disease, PSP progressive supranuclear palsy, PNFA progressive non-fluent aphasia, F familial, S sporadic, U family history undocumented a Indicates variants not previously associated with ALS, FTLD or PDB [7, 11, 17, 28, 29, 33]. For a complete description of SQSTM1 mutations, see Supplementary table 2…”

C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins

“…Ubiquitin- and p62-positive inclusions composed of c9RAN proteins are a neuropathological hallmark in c9FTD/ALS 14–18 , and mutations in p62 (refs. 30,31) and ubiquilin-2 (ref. 32) also result in ALS and FTD, indicating that UPS disruption may be a critical factor in c9FTD/ALS disease pathology.…”