REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31

Abstract

Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for REEP1 mutations and copy number variations. We identified 13 novel and 2 known REEP1 mutations in 16 familial and sporadic patients by direct sequencing analysis. Twelve out of 16 mutations were small insertions, deletions or splice site mutations. These changes would result in shifts of the open-reading-frame followed by premature termination of translation and haploinsufficiency. Interestingly, we identified two disease associated variations in the 3'-UTR of REEP1 that fell into highly conserved micro RNA binding sites. Copy number variation analysis in a subset of 133 HSP index patients revealed a large duplication of REEP1 that involved exons 2-7 in an Irish family. Clinically most SPG31 patients present with a pure spastic paraplegia; rare complicating features were restricted to symptoms or signs of peripheral nerve involvement. Interestingly, the distribution of age at onset suggested a bimodal pattern with the appearance of initial symptoms of disease either before the age of 20 years or after the age of 30 years. The overall mutation rate in our clinically heterogeneous sample was 3.0%; however, in the sub-sample of pure HSP REEP1 mutations accounted for 8.2% of all patients. These results firmly establish REEP1 as a relatively frequent autosomal dominant HSP gene for which genetic testing is warranted. We also establish haploinsufficiency as the main molecular genetic mechanism in SPG31, which should initiate and guide functional studies on REEP1 with a focus on loss-of-function mechanisms. Our results should be valid as a reference for mutation frequency, spectrum of REEP1 mutations, and clinical phenotypes associated with SPG31.

A total of 220 patients with autosomal dominant spastic paraplegia do not display mutations in the SLC33A1 gene (SPG42)

“…Mutations in the ATL1 and REEP1 gene had previously been excluded by direct sequencing and multiplex ligationdependent probe amplification (MLPA) at the following frequencies: SPG3A sequencing in 55% of cases, SPG3A MLPA in 85% and SPG31 (sequencing and MLPA) in 84% of cases. 7,9,[12][13][14] The HSP phenotype was pure in 125 (57%) and complicated in 95 (43%) patients. Informed consent was obtained in all cases.…”

“…17 This mutational class is frequent (B20%) in SPG4 and is also relevant for SPG31. 7,14,19 Both forms are associated with pure ADHSP. To assess quantitative changes in SLC33A1 copy number, MLPA was used but no rearrangements were identified.…”

“…Mutations in genes SPASTIN (MIM# 604277; SPG4, MIM# 182601), ATL1 (MIM# 606439; SPG3, MIM# 182600), KIF5A (MIM# 602821; SPG10, MIM# 604187) and REEP1 (MIM# 609139; SPG31, MIM# 610250) account for B40, B10, B3 and B8% of all ADHSP patients, respectively. 2,[5][6][7] The remaining HSP genes seem to be relatively rare. 8,9 Spastic paraplegia type 42 (SPG42, MIM# 612539) was recently mapped to the 3q24-26 chromosomal region in a single Chinese family presenting with pure ADHSP.…”

A recurrent deletion syndrome at chromosome bands 2p11.2-2p12 flanked by segmental duplications at the breakpoints and including REEP1

“…Nonsense variants in REEP1 causing haploinsufficiency/loss of function are responsible for autosomal dominant hereditary spastic paraplegia (HSP)-type SPG31 (OMIM 610250). 13,14 HSP-related features were seen in patient 1, the previous patient with the 9.4-Mbp deletion 2 and other patients with REEP1 deletions. 10,11 The age distribution for SPG31 shows a bimodal pattern of o20 and 430 years of age 13,14 leaving a possibility that HSP is not yet manifest in patient 1.…”

Demonstrating polymorphic miRNA-mediated gene regulation in vivo: Application to the g+6223G→A mutation of Texel sheep

“…At least 10 associations have been reported between complex disease and 39UTR SNPs predicted to alter miRNA target sites (Abelson et al 2005;Züchner et al 2006;Adams et al 2007;Mishra et al 2007;Sethupathy et al 2007;Tan et al 2007;Beetz et al 2008;Brendle et al 2008;Chin et al 2008;Kapeller et al 2008;Landi et al 2008;Lv et al 2008;Wang et al 2008;Jensen et al 2009). However, as pointed out by Sethupathy and Collins (2008), in most of these cases the evidence supporting the hypothesis was suggestive at best.…”