REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction.

Cyril Goizet, Christel Depienne, Giovanni Benard, Amir Boukhris, Emeline Mundwiller, Guilhem Solé, Isabelle Coupry, Julie Pilliod, Marie-Laure Martin-Négrier, Estelle Fedirko, Sylvie Forlani, Cécile Cazeneuve, Didier Hannequin, Perrine Charles, Imed Feki, Jean-François Pinel, Anne-Marie Ouvrard-Hernandez, Stanislas Lyonnet, Elisabeth Ollagnon-Roman, Jacqueline Yaouanq, Annick Toutain, Christelle Dussert, Bertrand Fontaine, Eric Leguern, Didier Lacombe, Alexandra Durr, Rodrigue Rossignol, Alexis Brice, Giovanni Stevanin
Hum. Mutat.. 2011-09-09; 32(10): 1118-1127
DOI: 10.1002/humu.21542

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Goizet C(1), Depienne C, Benard G, Boukhris A, Mundwiller E, Solé G, Coupry I,
Pilliod J, Martin-Négrier ML, Fedirko E, Forlani S, Cazeneuve C, Hannequin D,
Charles P, Feki I, Pinel JF, Ouvrard-Hernandez AM, Lyonnet S, Ollagnon-Roman E,
Yaouanq J, Toutain A, Dussert C, Fontaine B, Leguern E, Lacombe D, Durr A,
Rossignol R, Brice A, Stevanin G.

Author information:
(1)Université Bordeaux Segalen, Laboratoire Maladies Rares: Génétique et
Métabolisme, Bordeaux, France.

Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of
neurodegenerative disorders characterized at least by slowly progressive
spasticity of the lower limbs. Mutations in REEP1 were recently associated with a
pure dominant HSP, SPG31. We sequenced all exons of REEP1 and searched for
rearrangements by multiplex ligation-dependent probe amplification (MLPA) in a
large panel of 175 unrelated HSP index patients from kindreds with dominant
inheritance (AD-HSP), with either pure (n = 102) or complicated (n = 73) forms of
the disease, after exclusion of other known HSP genes. We identified 12 different
heterozygous mutations, including two exon deletions, associated with either a
pure or a complex phenotype. The overall mutation rate in our clinically
heterogeneous sample was 4.5% in French families with AD-HSP. The phenotype was
restricted to pyramidal signs in the lower limbs in most patients but nine had a
complex phenotype associating axonal peripheral neuropathy (= 5/11 patients)
including a Silver-like syndrome in one patient, and less frequently cerebellar
ataxia, tremor, dementia. Interestingly, we evidenced abnormal mitochondrial
network organization in fibroblasts of one patient in addition to defective
mitochondrial energy production in both fibroblasts and muscle, but whether these
anomalies are directly or indirectly related to the mutations remains uncertain.

© 2011 Wiley-Liss, Inc.

 

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