REEP1 (SPG31) found with recessive inheritance

Posted - May 2016 in Research Highlights

Previously associated only with dominant form

 

Complicated SPG31 HSP caused by a mutation in the REEP1 gene has now been found with recessive inheritance in a 5-year-old boy.

 

OBJECTIVE:

To identify the underlying genetic cause of a congenital neuropathy in a 5-year-old boy as part of a cohort of 32 patients from 23 families with genetically unresolved neuropathies.

 

METHODS:

We used autozygosity mapping coupled with next-generation sequencing to investigate a consanguineous family from Lebanon with 1 affected and 2 healthy children. Variants were investigated for segregation in the family by Sanger sequencing. A splice site mutation was further evaluated on the messenger RNA level by quantitative reverse transcription PCR. Subsequently, a larger cohort was specifically screened for receptor expression-enhancing protein 1 (REEP1) gene mutations.

 

RESULTS:

We detected a homozygous splice donor mutation in REEP1 (c.303+1-7GTAATAT>AC, p.F62Kfs23*; NM_022912) that cosegregated with the phenotype in the family, leading to complete skipping of exon 4 and a premature stop codon. The phenotype of the patient is similar to spinal muscular atrophy with respiratory distress type 1 (SMARD1) with additional distal arthrogryposis and involvement of the upper motor neuron manifested by pronounced hyperreflexia.

 

CONCLUSION:

To date, only dominant REEP1 mutations have been reported to be associated with a slowly progressive hereditary spastic paraplegia. The findings from our patient expand the phenotypical spectrum and the mode of inheritance of REEP1-associated disorders. Recessive mutations in REEP1 should be considered in the molecular genetic workup of patients with a neuromuscular disorder resembling SMARD1, especially if additional signs of upper motor neuron involvement and distal arthrogryposis are present.

 

SOURCE: Neurol Genet. 2015 Oct 22;1(4):e32. doi: 10.1212/NXG.0000000000000032. eCollection 2015. PMID: 27066569 [PubMed] PMCID: PMC4811389

 

Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy.

 

Schottmann G1, Seelow D1, Seifert F1, Morales-Gonzalez S1, Gill E1, von Au K1, von Moers A1, Stenzel W1, Schuelke M1.

 

1 Departments of Neuropediatrics (G.S., D.S., F.S., S.M.-G., E.G., M.S.) and Neuropediatrics/SPZ (K.v.A.), NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany; the Department of Neuropathology (W.S.), Charité-Universitätsmedizin Berlin, Germany; and the DRK Children’s Hospital Berlin (A.v.M.), Germany.

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