Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V.
The distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of neurodegenerative disorders affecting the lower motoneuron. In a family with both autosomal-dominant dHMN and dHMN type V (dHMN/dHMN-V) present in three generations, we excluded mutations in all genes known to be associated with a dHMN phenotype through Sanger sequencing and defined three potential loci through linkage analysis. Whole-exome sequencing of two affected individuals revealed a single candidate variant within the linking regions, i.e., a splice-site alteration in REEP1 (c.304-2A>G). A minigene assay confirmed complete loss of splice-acceptor functionality and skipping of the in-frame exon 5. The resulting mRNA is predicted to be expressed at normal levels and to encode an internally shortened protein (p.102_139del). Loss-of-function REEP1 mutations have previously been identified in dominant hereditary spastic paraplegia (HSP), a disease associated with upper-motoneuron pathology. Consistent with our clinical-genetic data, we show that REEP1 is strongly expressed in the lower motoneurons as well. Upon exogeneous overexpression in cell lines we observe a subcellular localization defect for p.102_139del that differs from that observed for the known HSP-associated missense mutation c.59C>A (p.Ala20Glu). Moreover, we show that p.102_139del, but not p.Ala20Glu, recruits atlastin-1, i.e., one of the REEP1 binding partners, to the altered sites of localization. These data corroborate the loss-of-function nature of REEP1 mutations in HSP and suggest that a different mechanism applies in REEP1-associated dHMN.
Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Germany.
Christian
C
Beetz
Thomas R
TR
Pieber
Nicole
N
Hertel
Maria
M
Schabhüttl
Carina
C
Fischer
Slave
S
Trajanoski
Elisabeth
E
Graf
Silke
S
Keiner
Ingo
I
Kurth
Thomas
T
Wieland
Rita-Eva
RE
Varga
Vincent
V
Timmerman
Mary M
MM
Reilly
Tim M
TM
Strom
Michaela
M
Auer-Grumbach
D002460:Cell Line; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000235:genetics*; D017422:Sequence Analysis, DNA
D026901:Membrane Transport Proteins; C495318:REEP1 protein, human