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Publications

Journal Article Epublish

PubMed: 39544688 DOI: 10.1002/jmd2.12424

The phenotypic spectrum of deficiency.

JIMD Rep 65(5):297-304

Authors: Baiba Lace, Eissa Faqeih, Namik Kaya, Zita Krumina, Johannes A Mayr, Ieva Micule, Nathan Thompson Wright, Melanie T Achleitner, Hanan AlQudairy, Sander Pajusalu, Janis Stavusis, Pawel Zayakin, Inna Inashkina

Affiliations

  • Riga East Clinical University Hospital Riga Latvia.
  • Institute of Clinical and Preventive Medicine, University of Latvia Riga Latvia.
  • Section of Medical Genetics Children's Specialist Hospital, King Fahad Medical City Riyadh Saudi Arabia.
  • Translational Genomics Department MBC: 26, Centre for Genomic Medicine Riyadh Saudi Arabia.
  • Department of Biology and Microbiology Riga Stradiņš University Riga Latvia.
  • University Children's Hospital, Laboratory Salzburger Landeskliniken Universitaetsklinikum of the Paracelsus Medical University Salzburg Salzburg Austria.
  • Department of Medical Genetics and Prenatal Diagnostics Children's University Hospital Riga Latvia.
  • Department of Chemistry and Biochemistry James Madison University Harrisonburg Virginia USA.
  • Department of Clinical Genetics, Genetics and Personalized Medicine Clinic Tartu University Hospital Tartu Estonia.
  • Department of Genetics and Personalized Medicine Institute of Clinical Medicine, Faculty of Medicine, University of Tartu Tartu Estonia.
  • Latvian Biomedical Research and Study Centre Riga Latvia.

Abstract

The gene product (protein PTCD3 or MRPS39) forms the entry channel of the mitochondrial small ribosomal subunit and binds to single-stranded mRNA. Here, we expand on the clinical manifestations of pathogenic variants by describing an early-onset patient with Leigh-like syndrome and two patients with milder form of disease, with combined oxidative phosphorylation deficiency. A 34-year-old male and his 33-year-old sister both have horizontal nystagmus, pronounced rough tremor, truncal ataxia, dysmetria, spasticity and hyperreflexia. The basal respiration rate decreased significantly for the male patient and his mother ( < 0.0001) compared to the controls. The whole genome sequencing analysis revealed two heterozygous variants in the : c.1182T>A, p.(Tyr394Ter) and c.805C>T, p.(His269Tyr). Tyr394Ter variant ablates the C-terminal half of the protein, including a significant portion of the central fold. In silico modelling for the variant His269Tyr shows that the inclusion of the slightly larger tyrosine sidechain is well tolerated, with no significant change in either the position or the movement of the surrounding area. The third case is a 9-year-old boy, who has a global developmental delay, central hypotonia, hyperreflexia and abnormal MRI. pathogenic variant c.538+4A>G was identified by whole exome sequencing. To test the variant's effect on splicing, an RT-PCR experiment was performed, which revealed skipping of an out-of-frame exon 7.