Abstract

OBJECTIVE: Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot-Marie-Tooth disease type 1A (CMT1A). To address this question the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of eight years. CMT1A is caused in most patients by a uniformly sized 1.5Mb duplication event involving the gene PMP22.METHODS: We genotyped DNA samples from 971 CMT1A patients on Illumina beadchips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal induced proliferation associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve and our functional studies identified and confirmed interacting proteins using co-immunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation.RESULTS: We identified significant association of four SNPs (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (P < 1*10-7 ). Co-immunoprecipitation and mass-spectroscopy studies identified beta-actin and MYH9 as SIPA1L2 binding partners. Further, we show that SIPA1L2 is part of a myelination-associated co-expressed network regulated by the master transcription factor SOX10. Importantly, in vitro knock-down of SIPA1L2 in Schwannoma cells lead to a significant reduction of PMP22 expression, hinting at a potential strategy for drug development.INTERPRETATION: offers a new pathway to therapeutic interventions. This article is protected by copyright. All rights reserved.

View details for PubMedID 30706531