title: 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.
authors.affiliation: Institute for Clinical Chemistry and Laboratory Diagnostics, University Hospital Jena, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Beetz
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.forename: Tine
authors.initials: T
authors.lastname: Deconinck
authors.forename: Khanh-Nhat
authors.initials: KN
authors.lastname: Tran-Viet
authors.forename: Hui
authors.initials: H
authors.lastname: Zhu
authors.forename: Berry P H
authors.initials: BP
authors.lastname: Kremer
authors.forename: Suzanna G M
authors.initials: SG
authors.lastname: Frints
authors.forename: Wendy A G
authors.initials: WA
authors.lastname: van Zelst-Stams
authors.forename: Paula
authors.initials: P
authors.lastname: Byrne
authors.forename: Susanne
authors.initials: S
authors.lastname: Otto
authors.forename: Anders O H
authors.initials: AO
authors.lastname: Nygren
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.forename: Katrien
authors.initials: K
authors.lastname: Smets
authors.forename: Berten
authors.initials: B
authors.lastname: Ceulemans
authors.forename: Bernard
authors.initials: B
authors.lastname: Dan
authors.forename: Narasimhan
authors.initials: N
authors.lastname: Nagan
authors.forename: Jan
authors.initials: J
authors.lastname: Kassubek
authors.forename: Sven
authors.initials: S
authors.lastname: Klimpe
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Henning
authors.initials: H
authors.lastname: Stolze
authors.forename: Hubert J M
authors.initials: HJ
authors.lastname: Smeets
authors.forename: Constance T R M
authors.initials: CT
authors.lastname: Schrander-Stumpel
authors.forename: Michael
authors.initials: M
authors.lastname: Hutchinson
authors.forename: Bart P
authors.initials: BP
authors.lastname: van de Warrenburg
authors.forename: Corey
authors.initials: C
authors.lastname: Braastad
authors.forename: Thomas
authors.initials: T
authors.lastname: Deufel
authors.forename: Margaret
authors.initials: M
authors.lastname: Pericak-Vance
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Peter
authors.initials: P
authors.lastname: de Jonghe
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*
chemical_list: D026901:Membrane Transport Proteins; C495318:REEP1 protein, human