Variation in SIPA1L2 is correlated with phenotype modification in Charcot– Marie– Tooth disease type 1A

for the Inherited Neuropathy Consortium

Research output: Contribution to journalArticle

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 8 years. CMT1A is caused in most patients by a uniformly sized 1.5 Mb 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 coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation. Results: We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (p < 1 × 10 −7 ). Coimmunoprecipitation and mass spectroscopy studies identified β-actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2 is part of a myelination-associated coexpressed network regulated by the master transcription factor SOX10. Importantly, in vitro knockdown of SIPA1L2 in Schwannoma cells led to a significant reduction of PMP22 expression, hinting at a potential strategy for drug development. Interpretation: SIPA1L2 is a potential genetic modifier of CMT1A phenotypic expressions and offers a new pathway to therapeutic interventions. ANN NEUROL 2019;85:316–330.

Original languageEnglish (US)
Pages (from-to)316-330
Number of pages15
JournalAnnals of Neurology
Volume85
Issue number3
DOIs
StatePublished - Mar 1 2019

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Charcot-Marie-Tooth Disease
Phenotype
Rare Diseases
SOXE Transcription Factors
Foot
Mass Spectrometry
Modifier Genes
Chromatin Immunoprecipitation
Neurilemmoma
Peripheral Nerves
Small Interfering RNA
Genes
Single Nucleotide Polymorphism
Actins
Immunohistochemistry
Genome
DNA
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Variation in SIPA1L2 is correlated with phenotype modification in Charcot– Marie– Tooth disease type 1A. / for the Inherited Neuropathy Consortium.

In: Annals of Neurology, Vol. 85, No. 3, 01.03.2019, p. 316-330.

Research output: Contribution to journalArticle

for the Inherited Neuropathy Consortium. / Variation in SIPA1L2 is correlated with phenotype modification in Charcot– Marie– Tooth disease type 1A. In: Annals of Neurology. 2019 ; Vol. 85, No. 3. pp. 316-330.
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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 8 years. CMT1A is caused in most patients by a uniformly sized 1.5 Mb 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 coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation. Results: We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (p < 1 × 10 −7 ). Coimmunoprecipitation and mass spectroscopy studies identified β-actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2 is part of a myelination-associated coexpressed network regulated by the master transcription factor SOX10. Importantly, in vitro knockdown of SIPA1L2 in Schwannoma cells led to a significant reduction of PMP22 expression, hinting at a potential strategy for drug development. Interpretation: SIPA1L2 is a potential genetic modifier of CMT1A phenotypic expressions and offers a new pathway to therapeutic interventions. ANN NEUROL 2019;85:316–330.",
author = "{for the Inherited Neuropathy Consortium} and Feifei Tao and Beecham, {Gary W} and Rebelo, {Adriana P.} and John Svaren and Blanton, {Susan H} and Moran, {John J.} and Camila Lopez-Anido and Morrow, {Jasper M.} and Lisa Abreu and Devon Rizzo and Kirk, {Callyn A.} and Xingyao Wu and Shawna Feely and Camiel Verhamme and {da Cunha Saporta}, Mario and Herrmann, {David N.} and Day, {John W.} and Sumner, {Charlotte J.} and Lloyd, {Thomas E.} and Jun Li and Yum, {Sabrina W.} and Franco Taroni and Frank Baas and Choi, {Byung Ok} and Davide Pareyson and Scherer, {Steven S.} and Reilly, {Mary M.} and Shy, {Michael E.} and Zuchner, {Stephan L}",
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T1 - Variation in SIPA1L2 is correlated with phenotype modification in Charcot– Marie– Tooth disease type 1A

AU - for the Inherited Neuropathy Consortium

AU - Tao, Feifei

AU - Beecham, Gary W

AU - Rebelo, Adriana P.

AU - Svaren, John

AU - Blanton, Susan H

AU - Moran, John J.

AU - Lopez-Anido, Camila

AU - Morrow, Jasper M.

AU - Abreu, Lisa

AU - Rizzo, Devon

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AU - da Cunha Saporta, Mario

AU - Herrmann, David N.

AU - Day, John W.

AU - Sumner, Charlotte J.

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AU - Li, Jun

AU - Yum, Sabrina W.

AU - Taroni, Franco

AU - Baas, Frank

AU - Choi, Byung Ok

AU - Pareyson, Davide

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