Two Novel Mutations in the SLC25A4 Gene in a Patient with Mitochondrial Myopathy

Abstract

In a 28-year-old male with a mild mitochondrial myopathy manifesting as exercise intolerance and early signs of cardiomyopathy without muscle weakness or ophthalmoplegia, we identified two novel mutations in the SLC25A4 gene: c.707G>C in exon 3 (p.(R236P)) and c.116_137del in exon 2 (p.(Q39Lfs*14)). Serum lactate levels at rest were elevated (12.7 mM). Both the patient’s father and brother were heterozygous carriers of the c.707G>C mutation and were asymptomatic. The second mutation causes a 22 bp deletion leading to a frame shift likely giving rise to a premature stop codon and nonsense-mediated decay (NMD). The segregation of the mutations could not be tested directly as the mother had died before. However, indirect evidence from NMD experiments showed that the two mutations were situated on two different alleles in the patient. This case is unique compared to other previously reported patients with either progressive external ophthalmoplegia (PEO) or clear hypertrophic cardiomyopathy with exercise intolerance and/or muscle weakness carrying recessive mutations leading to a complete absence of the SLC25A4 protein. Most likely in our patient, although severely reduced, SLC25A4 is still partially present and functional.

Competing interests: None declared

Appendices

Synopsis

Two novel recessive SLC25A4 mutations leading to a relatively mild phenotype without progressive external ophthalmoplegia.

Details of the Contributions of Individual Authors

IKK set up the SLC25A4 sequencing and wrote the paper. She is the guarantor. MdV provided medical information of the patient and wrote part of the paper. HB, HS, LD, LS, and RW were involved in the initial investigation and further characterization of the biochemical phenotype of the patient. FV was involved in the patient care. GN created models to assess the impact of the SLC25A4 mutations on protein structure. HS was involved in writing the paper. AH performed the NMD experiments and was involved in the setup of the SLC25A4 sequencing. BB wrote the paper and is also a guarantor. All authors have critically revised the paper.

Name of One Author Who Serves as Guarantor

Irene Körver-Keularts

Conflict of Interest

Irene Körver-Keularts, Marianne de Visser, Henk Bakker, Ronald Wanders, Fleur Vansenne, Jasper Scholte, Bert Dorland, Gerry Nicolaes, Leo Spaapen, Bert Smeets, Alexandra Hendrickx, and Bianca van den Bosch have no conflict of interest.

There are no competing interests.

The author(s) confirm(s) independence from the sponsors.

Compliance with Ethics Guidelines

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from the patient and his family for being included in the study.