RESUMO
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 ß-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.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Pé/fisiopatologia , Proteínas Ativadoras de GTPase/genética , Genes Modificadores/genética , Debilidade Muscular/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/fisiopatologia , Proteínas da Mielina/genética , Neurilemoma/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Ratos , Índice de Gravidade de Doença , Adulto JovemRESUMO
INTRODUCTION: This study evaluates carpal tunnel syndrome (CTS) symptom severity, functional status, and outcome of CTS therapies in patients with inherited neuropathies. METHODS: Validated questionnaires were used to compare symptom severity and functional status in patients with and without a diagnosis of CTS and a diagnosis of an inherited neuropathy. RESULTS: 309 patients with inherited neuropathies participated in this study. The CTS symptom severity score (SSS) was found to be the most useful tool in assessing CTS severity in patients with inherited neuropathy. Splint therapy and surgery were associated with significant improvement in carpal tunnel symptoms as measured through the SSS. DISCUSSION: This study provides insight into the assessment of CTS symptom severity and patient-reported outcomes to CTS therapy in individuals with inherited neuropathies. The SSS appears useful for evaluation of CTS symptoms and patient-reported outcomes following CTS interventions in individuals with inherited neuropathies. Muscle Nerve 57: 388-394, 2018.