J Clin Neurol.  2011 Mar;7(1):25-30. 10.3988/jcn.2011.7.1.25.

SLC25A4 and C10ORF2 Mutations in Autosomal Dominant Progressive External Ophthalmoplegia

• Park KP
• Kim HS
• Kim ES
• Park YE
• Lee CH
• Kim DS

• KMID: 1452569
• DOI: http://doi.org/10.3988/jcn.2011.7.1.25

Abstract

BACKGROUND AND PURPOSE
Progressive external ophthalmoplegia (PEO) with Mendelian inheritance is a heterogeneous group of diseases associated with multiple deletions of mitochondrial DNA (mtDNA), which results from the disturbed replication and maintenance of mtDNA secondary to the mutations of nuclear genes including POLG, SLC25A4, C10ORF2, POLG2, OPA1, and RRM2B. The aim of this study was to identify the genetic defects underlying the pathology and clinical features in two Korean kindreds with autosomal dominant PEO.
METHODS
Two pathologically proven PEO patients with a clear autosomal dominant pattern of inheritance were selected. To exclude a large-scale rearrangement, a long-range polymerase chain reaction (PCR) was performed using DNA extracted from biopsied muscle tissue taken from each patient. All coding regions and exon-intron boundaries of POLG, SLC25A4, C10ORF2, and POLG2 were amplified by PCR and directly sequenced.
RESULTS
One patient showed multiple deletions of mtDNA on long-range PCR analysis, and two known heterozygous missense mutations in SLC25A4 (p.Asp104Gly) and C10ORF2 (p.Glu479Lys) were identified in each patient. The p.Asp104Gly mutation in SLC25A4 was identified in the patient with an early onset, slowly progressive, pure PEO phenotype, while the p.Glu479Lys mutation in C10ORF2 was identified in the other patient, with a late-onset disease and PEO plus phenotype.
CONCLUSIONS
Two mutations affecting nuclear genes were identified in Korean patients with autosomal dominant PEO. Further studies are necessary to identify the clear pathogenetic mechanisms and establish genotype-phenotype correlations in autosomal dominant PEO.

Keyword

autosomal dominant trait; progressive external ophthalmoplegia; mutation; SLC25A4; C10ORF2

MeSH Terms

Clinical Coding
DNA
DNA, Mitochondrial
Genetic Association Studies
Humans
Muscles
Mutation, Missense
Ophthalmoplegia, Chronic Progressive External
Phenotype
Polymerase Chain Reaction
Wills
DNA
DNA, Mitochondrial

Figure

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  Fig. 1 Mutations identified in the patients. A: Patient 1: a heterozygous point mutation, c.311A>G (p.Asp104Gly), was identified in exon 2 of SLC25A4. B: Patient 2: a heterozygous point mutation, c.1435G>A (p.Glu479Lys), was identified in exon 2 of C10ORF2.

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  Fig. 2 Family pedigrees of patients 1 (A) and 2 (B).

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  Fig. 3 Muscle biopsy findings of patients 1 (A-D) and 2 (E-H) showing multiple cytochrome-C-oxidase-negative ragged red fibers. Samples in (A) and (E) are stained with hematoxylin and eosin, those in (B) and (F) are stained with modified Gomori trichrome, those in (C) and (G) are stained for succinate dehydrogenase, and those in (D) and (H) are stained for cytochrome (C) oxidase. The white bar indicates 50 µm.

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