A novel homozygous MPV17 mutation in two families with axonal sensorimotor polyneuropathy
Yu-Ri Choi1, Young Bin Hong2, Sung-Chul Jung3
1Department of Biochemistry, Ewha Womans University School of Medicine, Seoul, Korea. power_upup@naver.com.
Background:
Mutations 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.
Methods:
Whole 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.
Results:
A 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.
Conclusion:
We 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.
Insights
Mutations in the MPV17 gene cause a rare neuropathy. This study identifies a new MPV17 mutation in patients with axonal sensorimotor polyneuropathy, expanding the known disease spectrum.
Area of Science:
- Genetics
- Neurology
- Mitochondrial Biology
Background:
- Mutations in MPV17 cause mitochondrial DNA depletion syndrome 6 (MTDPS6), also known as Navajo neurohepatopathy (NNH).
- MTDPS6 typically presents with infantile liver failure and sometimes neurological issues.
Purpose of the Study:
- To identify the genetic cause of neuropathy in two unrelated patients.
- To expand the understanding of MPV17-related disorders.
Main Methods:
- Whole exome sequencing (WES) was used to identify the causative gene.
- Clinical assessments, biochemical analysis, and in vitro assays with mouse motor neuronal cells were performed.
Main Results:
- A novel homozygous MPV17 mutation (p.R41Q) was identified in both patients.
- Patients presented with axonal sensorimotor polyneuropathy, distinct from typical MTDPS6 liver/brain involvement.
- MPV17 abrogation and mutant protein expression impaired neuronal cell integrity and proliferation.
Conclusions:
- A novel MPV17 mutation causes axonal sensorimotor polyneuropathy without hepatoencephalopathy.
- This expands the clinical spectrum of MPV17-related disorders.
- MPV17 gene screening is recommended for axonal peripheral neuropathies.
