Bi-allelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency

Thomas H. B., Demain L. A., Cabrera-Orefice A., Schrauwen I., Shamseldin H. E., Rea A., ...Daha Fazla

American Journal of Human Genetics, cilt.112, sa.4, ss.952-962, 2025 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 112 Sayı: 4
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1016/j.ajhg.2025.02.005
  • Dergi Adı: American Journal of Human Genetics
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, International Bibliography of Social Sciences, BIOSIS, CAB Abstracts, Chemical Abstracts Core, CINAHL, EMBASE, Veterinary Science Database, Nature Index
  • Sayfa Sayıları: ss.952-962
  • Anahtar Kelimeler: combined oxidative phosphorylation deficiency, learning disability, leukodystrophy, mitochondria, mitoribosome, MRPL49, Perrault syndrome, primary ovarian insufficiency, rare disease, sensorineural hearing loss
  • Çukurova Üniversitesi Adresli: Evet

Özet

Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder that is clinically and genetically heterogeneous. Genome sequencing identified bi-allelic MRPL49 variants in individuals from nine unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly, and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small mitochondrial ribosomal subunits and a more pronounced reduction of the large mitochondrial ribosomal subunits. There was no evidence of altered mitoribosomal assembly. The reductions in levels of oxidative phosphorylation (OXPHOS) enzyme complexes I and IV are consistent with a form of COXPD associated with bi-allelic MRPL49 variants, expanding the understanding of how disruption of the mitochondrial ribosomal large subunit results in multisystem phenotypes.