A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene

Kennerson, Marina; Yiu, Eppie M; Chuang, David T.; Kidambi, Aditi; Tso, Shih Chia; Ly, Carolyn; Chaudhry, Rabia; Drew, Alexander P.; Rance, Gary; Delatycki, Martin B.; Züchner, Stephan; Ryan, Monique M.; Nicholson, Garth A.

doi:10.1093/hmg/dds557

Cited by 68 publications

(56 citation statements)

References 45 publications

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“…8 Candidate variants were screened through 1,000 neurologically normal chromosomes as previously described and also queried against 30 in-house exomes from neurologically normal controls. 8 Variants were annotated using ANNOVAR software. 9 …”

Section: Methodsmentioning

confidence: 99%

MORC2 mutations cause axonal Charcot–Marie–Tooth disease with pyramidal signs

Albulym

Kennerson

Harms

et al. 2016

Annals of Neurology

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Objective To use linkage analysis and whole exome sequencing to identify the genetic mutation in a multigenerational Australian family with Charcot–Marie–Tooth disease type 2 (CMT2) and pyramidal signs. Methods Genome-wide linkage analysis was performed to map the locus. Whole exome sequencing was undertaken on selected individuals (3 affected, 1 normal), and segregation analysis and mutation screening were carried out using high-resolution melt analysis. The GEM.app database was queried to identify additional families with mutations. Results Significant linkage (2-point LOD score ≥ +3) and haplotype analysis mapped a new locus for CMT2 and pyramidal signs to a 6.6Mb interval on chromosome 22q12.1–q12.3. Whole exome sequencing identified a novel mutation (p.R252W) in the microrchidia CW-type zinc finger 2 (MORC2) gene mapping within the linkage region. The mutation fully segregated with the disease phenotype in the family. Screening additional families and querying unsolved CMT2 exomes, we identified the p.R252W mutation in 2 unrelated early onset CMT2 families and a second mutation p.E236G in 2 unrelated CMT2 families. Both the mutations occurred at highly conserved amino acid residues and were absent in the normal population. Interpretation We have identified a new locus in which MORC2 mutations are the likely pathogenic cause of CMT2 and pyramidal signs in these families. MORC2 encodes the human CW-type zinc finger 2 protein, which is a chromatin modifier involved in the regulation of DNA repair as well as gene transcription.

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Section: Methodsmentioning

confidence: 99%

MORC2 mutations cause axonal Charcot–Marie–Tooth disease with pyramidal signs

Albulym

Kennerson

Harms

et al. 2016

Annals of Neurology

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“…Previously, a missense mutation in the PDK3 gene (p.R158H) was identified in an Australian family causing CMTX6 (Kennerson et al, ) . All males with the mutation had progressive distal weakness, gait disturbance, and sensory loss.…”

Section: Introductionmentioning

confidence: 99%

X‐linked Charcot‐Marie‐Tooth disease type 6 (CMTX6) patients with a p.R158H mutation in the pyruvate dehydrogenase kinase isoenzyme 3 gene

Kennerson

Kim

Siddell

et al. 2016

J Peripheral Nervous Sys

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Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. Mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene have been found to cause X-linked dominant CMT type 6 (CMTX6). This study identified the p.R158H PDK3 mutation after screening 67 probable X-linked CMT families. The mutation fully segregated with the phenotype, and genotyping the family indicated the mutation arose on a different haplotype compared with the original Australian CMTX6 family. Results of bisulphite sequencing suggest that methylated deamination of a CpG dinucleotide may cause the recurrent p.R158H mutation. The frequency of the p.R158H PDK3 mutation in Koreans is very rare. Magnetic resonance imaging revealed fatty infiltration involving distal muscles in the lower extremities. In addition, fatty infiltrations were predominantly observed in the soleus muscles, with a lesser extent in tibialis anterior muscles. This differs from demyelinating CMT1A patients and is similar to axonal CMT2A patients. The clinical, neuroimaging, and electrophysiological findings from a second CMTX6 family with the p.R158H PDK3 mutation were similar to the axonal neuropathy reported in the Australian family.

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“…Cx32 is localized in non-compacted myelin and forms functional channels that allow for the rapid transport of ions and small nutrients between coupled cells by radial migration through the myelin layers (53,54). The genes for three additional X-linked forms of CMT have been identified: AIFM1 is associated with CMTX4 or Cowchok syndrome which involves hearing loss and cognitive impairment in addition to neuropathy (55); PRPS1 is allelic to Arts syndrome and is characterized by neuropathy, optic atrophy and hearing loss (56); and PDK3 is the gene responsible for CMTX6 (57).…”

Section: Cmt2: Axonal Neuropathiesmentioning

confidence: 99%

Charcot–Marie–Tooth disease and pathways to molecular based therapies

Harel

Lupski

2014

Clinical Genetics

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The discovery in 1991 that chromosome 17p12 duplication is associated with Charcot-Marie-Tooth (CMT) disease marked the beginning of an era of molecular insight into this disorder, which encompasses the peripheral motor and sensory neuropathies. A mere two decades later, over 40 subtypes of CMT have been molecularly defined and many have been extensively studied in vitro and in animal models, providing the framework for a more comprehensive understanding of the biological pathways dictating myelination, axonal dynamics, and axon-glia interactions. The advent of next-generation sequencing technologies offers opportunities in both research and clinical settings for gene discovery, further molecular understanding and diagnosis, and calls for modifications of the existing algorithms guiding genetic testing. Although treatment is mainly supportive at this time, advances in this field are anticipated as the molecular basis of CMT is unraveled.

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A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene

Cited by 68 publications

References 45 publications

MORC2 mutations cause axonal Charcot–Marie–Tooth disease with pyramidal signs

MORC2 mutations cause axonal Charcot–Marie–Tooth disease with pyramidal signs

X‐linked Charcot‐Marie‐Tooth disease type 6 (CMTX6) patients with a p.R158H mutation in the pyruvate dehydrogenase kinase isoenzyme 3 gene

Charcot–Marie–Tooth disease and pathways to molecular based therapies

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