A novel homozygous MPV17 mutation in two families with axonal sensorimotor polyneuropathy.

Yu-Ri Choi,Jinho Lee,Young Bin Hong,Sang-Beom Kim,Hyung Jun Park,Heasoo Koo,Ji-Su Lee,So-Youn Woo,Ki Wha Chung,Dong Hwan Jwa,Namhee Jung,Sung-Chul Jung,Ye Jin Kim,Byung-Ok Choi,Ja Hyun Lee

doi:10.1186/s12883-015-0430-1

Abstract

BackgroundMutations in MPV17 cause the autosomal recessive disorder mitochondrial DNA depletion syndrome 6 (MTDPS6), also called Navajo neurohepatopathy (NNH). Clinical features of MTDPS6 is infantile onset of progressive liver failure with seldom development of progressive neurologic involvement.MethodsWhole exome sequencing (WES) was performed to isolate the causative gene of two unrelated neuropathy patients (9 and 13 years of age) with onset of the syndrome. Clinical assessments and biochemical analysis were performed.ResultsA novel homozygous mutation (p.R41Q) in MPV17 was found by WES in both patients. Both showed axonal sensorimotor polyneuropathy without liver and brain involvement, which is neurophysiologically similar to axonal Charcot-Marie-Tooth disease (CMT). A distal sural nerve biopsy showed an almost complete loss of the large and medium-sized myelinated fibers compatible with axonal neuropathy. An in vitro assay using mouse motor neuronal cells demonstrated that the abrogation of MPV17 significantly affected cell integrity. In addition, the expression of the mutant protein affected cell proliferation. These results imply that both the loss of normal function of MPV17 and the gain of detrimental effects of the mutant protein might affect neuronal function.ConclusionWe report a novel homozygous mutation in MPV17 from two unrelated patients harboring axonal sensorimotor polyneuropathy without hepatoencephalopathy. This report expands the clinical spectrum of diseases caused by mutations of MPV17, and we recommend MPV17 gene screening for axonal peripheral neuropathies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-015-0430-1) contains supplementary material, which is available to authorized users.

Highlights

Mutations in MPV17 cause the autosomal recessive disorder mitochondrial DNA depletion syndrome 6 (MTDPS6), called Navajo neurohepatopathy (NNH)
After filtering the Whole exome sequencing (WES) data for 3 members in each family (Fig. 1), a novel homozygous mutation c.122G> A (p.R41Q) in MPV17 was identified in both families (Fig. 1b)
More than 40 functionally significant variants were found in ~70 Charcot-Marie-Tooth disease (CMT)- and ~15 MTDPS-related genes, they were not considered the genetic cause, except for the MPV17 mutation, because they were found in the controls or noncosegregated with affected individuals (Additional file 1: Table S3 and S4)

Summary

Introduction

Mutations in MPV17 cause the autosomal recessive disorder mitochondrial DNA depletion syndrome 6 (MTDPS6), called Navajo neurohepatopathy (NNH). Mutations in MPV17 cause mitochondrial DNA depletion syndrome 6 (MTDPS6) (NNH; MIM #256810), known as Navajo neurohepatopathy, an autosomal, recessive, multi-system disorder [1]. The mice exhibited sensorineural deafness due to severe degeneration of the inner ear, and with associated apoptosis of the outer hair cells [4,5,6]. These results imply the significance of MPV17 in cellular integrity. In the absence of MPV17, yeast cells became more vulnerable to metabolic or oxidative stresses [7]

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