Titel: Deciphering MALSU1 in a consanguineous family with mitochondrial cardiomyopathy
ID: P-MonoG-155
Art: Postertalk
Redezeit: 2 min
Session: Poster Session

Referent: Laura Holthöfer (Mainz/DE), Mareike Selig (Mainz/DE)

Abstract - Text


Clinical description: We describe a consanguineous family with two brothers that show the clinical picture of a mitochondrial cardiomyopathy. The older boy has a history of learning difficulties but was considered as healthy until the age of 17. He then showed signs of a decompensated heart insufficiency and was diagnosed with non-compaction cardiomyopathy (LVNC). After hospitalisation with STEMI and a cardiogenic shock he died at the age of 19. The younger brother had been diagnosed with hypertrophic cardiomyopathy (HCM) at the age of 3 years. He also showed learning difficulties. At the age of 16 he showed progressive heart insufficiency. The family´s third child is completely healthy.

Methods: We undertook targeted next-generation sequencing (NGS) and searched for variants in a set of genes known to be causative for cardiomyopathy including mitochondrial encoded genes using the patients´ DNA isolated from whole blood. Furthermore, we sequenced the entire mitochondrial DNA (mtDNA) from urine sediment. Putative pathogenic variants were not detected, so we searched for variants in candidate genes causing mitochondriopathies. Available muscle biopsies from the left quadriceps muscle, the heart and skin biopsies were investigated by standard histological and electron microscopic techniques. The expression of various proteins was determined by immunohistochemistry and WesternBlot. Using the Seahorse Technique we analysed the activity of combined oxidative phosphorylation (OXPHOS).

Results: A homozygous missense variant in MALSU1 (C7orf30) was detected in genomic DNA of the two patients. Both parents and the healthy brother were identified as heterozygous carriers. MALSU1 encodes an assembly and stability factor of the large subunit of the mitochondrial ribosomes (mt-LSU), suggesting a critical role in mitochondrial translation for MALSU1. Protein modelling suggested substantial destabilization of MALSU 1 through the missense variant found in the family. Western blot analysis confirmed significant reduction of protein expression in cells of the two homozygous family members. Comparative seahorse analysis of fibroblasts of the two homozygous and the heterozygous brother showed a decrease in mitochondrial activity in the homozygous samples but not in the heterozygous sample. Ongoing Western blot analysis of mitochontrial translated proteins versus cytosolic synthesized proteins will show if the MALSU 1 variant influences mitrochondrial protein synthesis.

Conclusion: Mutations in mito-ribosomal proteins are a common cause of mitochondrial protein synthesis deficiencies. Here, we provide further evidence for MALSU1 to likely play a role in mitochondriopathies. Further functional studies are warranted to assess the functional role.