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.

Fig. 1

REEP1 mutations identified to date. Mutations are distributed over the entire gene except exon 3. The grey bar indicates a partial duplication in family I1018, which starts in intron 1 and reaches beyond the 3′-end of the coding sequence. TM: transmembrane domain, DP1: domain with similarity to the human DP1 gene. ^*mutation reported previously (Zuchner et al., 2006b).

Fig. 2

Pedigree of SPG31 families identified in the present study. Shaded symbols denote affected individuals, open symbols indicate unaffected individuals; unaffected carriers are marked by a vertical slash, obligate carriers of unknown clinical status by a dot and deceased family members by a diagonal slash.‘+’ tested mutation carriers.

Fig. 3

Age at onset (AAO) in SPG3A, SPG4 and SPG31 HSP plotted against frequency. The majority of SPG3A patients have an AAO before age 10 years, whereas SPG4 may start much later. SPG31 has an early onset, but about 15% of patients have an AAO after 30 suggesting a bi-modal distribution.