Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia

Typhaine Esteves, Alexandra Durr, Emeline Mundwiller, José L. Loureiro, Maxime Boutry, Michael A. Gonzalez, Julie Gauthier, Khalid H. El-Hachimi, Christel Depienne, Marie Paule Muriel, Rafael F. Acosta Lebrigio, Marion Gaussen, Anne Noreau, Fiorella Speziani, Alexandre Dionne-Laporte, Jean François Deleuze, Patrick Dion, Paula Coutinho, Guy A. Rouleau, Stephan ZuchnerAlexis Brice, Giovanni Stevanin, Frédéric Darios

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)268-277
Number of pages10
JournalAmerican journal of human genetics
Issue number2
StatePublished - Feb 6 2014

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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