Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy. (December 2015)

• Record Type: Journal Article
• Authors: Schottmann, Gudrun; Seelow, Dominik; Seifert, Franziska; Morales-Gonzalez, Susanne; Gill, Esther; von Au, Katja; von Moers, Arpad; Stenzel, Werner; Schuelke, Markus
• Is Part Of: Neurology. Volume 1:Number 4(2015)
• Publication Date: 2015-12
• Subjects: Neurogenetics -- Periodicals; 616.80442
• DOI: 10.1212/NXG.0000000000000032
• Languages: English
• ISSNs: 2376-7839

Abstract

Abstract : 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.