Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis

作者：Teyssou Elisa; Chartier Laura; Amador Maria Del Mar; Lam Roselina; Lautrette Geraldine; Nicol Marie; Machat Selma; Da Barroca Sandra; Moigneu Carine; Mairey Mathilde; Larmonier Thierry; Saker Safaa; Dussert Christelle; Forlani Sylvie; Fontaine Bertrand; Seilhean Danielle; Bohl Delphine; Boillee Severine; Meininger Vincent; Couratier Philippe; Salachas Francois; Stevanin Giovanni; Millecamps Stephanie

来源：Neurobiology of Aging, 2017, 58: 239.e11.

DOI：10.1016/j.neurobiolaging.2017.06.018

• Motor neuron disease
• X-linked ALS
• FTD
• Proteolysis regulation
• Incomplete penetrance
• X inactivation
• Dimerization

Mutations in UBQLN2 have been associated with rare cases of X-linked juvenile and adult forms of amyotrophic lateral sclerosis (ALS) and ALS linked to frontotemporal dementia (FTD). Here, we report 1 known (c.1489C>T, p.Pro497Ser, P497S) and 3 novel (c.1481C>T, p.Pro494Leu, P494L; c.1498C>T, p.Pro500Ser, P500S; and c.1516C>G, p.Pro506Ala, P506A) missense mutations in the PXX domain of UBQLN2 in familial motor neuron diseases including ALS and spastic paraplegia (SP). A novel missense mutation (c.1462G>A, p.Ala488Thr, A488T) adjacent to this hotspot UBQLN2 domain was identified in a sporadic case of ALS. These mutations are conserved in mammals, are absent from ExAC and gnomAD browsers, and are predicted to be deleterious by SIFT in silico analysis. Patient lymphoblasts carrying a UBQLN2 mutation showed absence of ubiquilin-2 accumulation, disrupted binding with HSP70, and impaired autophagic pathway. Our results confirm the role of PXX repeat in ALS pathogenesis, show that UBQLN2-linked disease can manifest like a SP phenotype, evidence a highly reduced disease penetrance in females carrying UBQLN2 mutations, which is important information for genetic counseling, and underline the pivotal role of ubiquilin-2 in proteolysis regulation pathways.

• 出版日期2017-10