Loss of Association of REEP2 with Membranes Leads to Hereditary Spastic Paraplegia

Abstract

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurological conditions. Their main pathogenic mechanisms are thought to involve alterations in endomembrane trafficking, mitochondrial function, and lipid metabolism. With a combination of whole-genome mapping and exome sequencing, we identified three mutations in REEP2 in two families with HSP: a missense variant (c.107T>A [p.Val36Glu]) that segregated in the heterozygous state in a family with autosomal-dominant inheritance and a missense change (c.215T>A [p.Phe72Tyr]) that segregated in trans with a splice site mutation (c.105+3G>T) in a family with autosomal-recessive transmission. REEP2 belongs to a family of proteins that shape the endoplasmic reticulum, an organelle that was altered in fibroblasts from an affected subject. In vitro, the p.Val36Glu variant in the autosomal-dominant family had a dominant-negative effect; it inhibited the normal binding of wild-type REEP2 to membranes. The missense substitution p.Phe72Tyr, in the recessive family, decreased the affinity of the mutant protein for membranes that, together with the splice site mutation, is expected to cause complete loss of REEP2 function. Our findings illustrate how dominant and recessive inheritance can be explained by the effects and nature of mutations in the same gene. They have also important implications for genetic diagnosis and counseling in clinical practice because of the association of various modes of inheritance to this new clinico-genetic entity.

Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia

“…10 Our results show that KIF1A variants must be considered in patients with HSP, regardless of the mode of inheritance. The gene REEP2 was also recently associated with both dominant and recessive HSP, 24 both inheritance types being classified under SPG72. 25 Therefore, we suggest that HSP caused by dominant KIF1A variants be classified in the same group as HSP caused by recessive KIF1A variants, that is, SPG30.…”

Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration

“…Western blotting was performed as described previously (Esteves et al, 2014). Signals were visualized with a chemiluminescence substrate (SuperSignal West Dura), or acquired with an Odyssey ClX (Li-COR).…”

Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms

“…Very recently, 15 candidate genes for ARHSP were reported and the assigned locus for HSP increased up to SPG72 (Esteves et al, 2014;Novarino et al, 2014) (Fig. 2, Tables 1 and 2).…”

“…In affected members of a large French family with ADHSP, it has been identified a heterozygous missense mutation in the REEP2 gene (Esteves et al, 2014) (Tables 1 and 2). ARHSP Forty-eight SPG loci and 41 genes responsible for ARHSP have been identified so far. Several other ARHSP loci, namely SPG14 (Vazza et al, 2000), SPG23 (Blumen et al, 2003), SPG24 (Hodgkinson et al, 2002), SPG25 (Zortea et al, 2002), SPG27 (Meijer et al, 2004;Ribaï et al, 2006), SPG32 (Stevanin et al, 2007a), and SPG45 (Dursun et al, 2009), have been identified but pathological genes are yet unknown (Tables 1 and 2).…”