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 L ZuchnerAlexis Brice, Giovanni Stevanin, Frédéric Darios

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)268-277
Number of pages10
JournalAmerican Journal of Human Genetics
Volume94
Issue number2
DOIs
StatePublished - Feb 6 2014

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Hereditary Spastic Paraplegia
Mutation
Membranes
Exome
Chromosome Mapping
Genetic Counseling
Mutant Proteins
Lipid Metabolism
Endoplasmic Reticulum
Organelles
Fibroblasts
Genes
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Esteves, T., Durr, A., Mundwiller, E., Loureiro, J. L., Boutry, M., Gonzalez, M. A., ... Darios, F. (2014). Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia. American Journal of Human Genetics, 94(2), 268-277. https://doi.org/10.1016/j.ajhg.2013.12.005

Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia. / Esteves, Typhaine; Durr, Alexandra; Mundwiller, Emeline; Loureiro, José L.; Boutry, Maxime; Gonzalez, Michael A.; Gauthier, Julie; El-Hachimi, Khalid H.; Depienne, Christel; Muriel, Marie Paule; Acosta Lebrigio, Rafael F.; Gaussen, Marion; Noreau, Anne; Speziani, Fiorella; Dionne-Laporte, Alexandre; Deleuze, Jean François; Dion, Patrick; Coutinho, Paula; Rouleau, Guy A.; Zuchner, Stephan L; Brice, Alexis; Stevanin, Giovanni; Darios, Frédéric.

In: American Journal of Human Genetics, Vol. 94, No. 2, 06.02.2014, p. 268-277.

Research output: Contribution to journalArticle

Esteves, T, Durr, A, Mundwiller, E, Loureiro, JL, Boutry, M, Gonzalez, MA, Gauthier, J, El-Hachimi, KH, Depienne, C, Muriel, MP, Acosta Lebrigio, RF, Gaussen, M, Noreau, A, Speziani, F, Dionne-Laporte, A, Deleuze, JF, Dion, P, Coutinho, P, Rouleau, GA, Zuchner, SL, Brice, A, Stevanin, G & Darios, F 2014, 'Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia', American Journal of Human Genetics, vol. 94, no. 2, pp. 268-277. https://doi.org/10.1016/j.ajhg.2013.12.005
Esteves, Typhaine ; Durr, Alexandra ; Mundwiller, Emeline ; Loureiro, José L. ; Boutry, Maxime ; Gonzalez, Michael A. ; Gauthier, Julie ; El-Hachimi, Khalid H. ; Depienne, Christel ; Muriel, Marie Paule ; Acosta Lebrigio, Rafael F. ; Gaussen, Marion ; Noreau, Anne ; Speziani, Fiorella ; Dionne-Laporte, Alexandre ; Deleuze, Jean François ; Dion, Patrick ; Coutinho, Paula ; Rouleau, Guy A. ; Zuchner, Stephan L ; Brice, Alexis ; Stevanin, Giovanni ; Darios, Frédéric. / Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia. In: American Journal of Human Genetics. 2014 ; Vol. 94, No. 2. pp. 268-277.
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AU - Durr, Alexandra

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AU - Loureiro, José L.

AU - Boutry, Maxime

AU - Gonzalez, Michael A.

AU - Gauthier, Julie

AU - El-Hachimi, Khalid H.

AU - Depienne, Christel

AU - Muriel, Marie Paule

AU - Acosta Lebrigio, Rafael F.

AU - Gaussen, Marion

AU - Noreau, Anne

AU - Speziani, Fiorella

AU - Dionne-Laporte, Alexandre

AU - Deleuze, Jean François

AU - Dion, Patrick

AU - Coutinho, Paula

AU - Rouleau, Guy A.

AU - Zuchner, Stephan L

AU - Brice, Alexis

AU - Stevanin, Giovanni

AU - Darios, Frédéric

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N2 - 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.

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