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 β‐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.

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