A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients.
Musa S1, Eyaid W2, Kamer K3,4, Ali R1, Al-Mureikhi M1, Shahbeck N1, Al Mesaifri F1, Makhseed N5, Mohamed Z6, AlShehhi WA7, Mootha VK3,4, Juusola J8, Ben-Omran T9.
1 Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
2 Department of Paediatrics, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
3 Howard Hughes Medical Institute, Chevy Chase, MD, USA.
4 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
5 Department of Pediatrics, Jahra Hospital, Kuwait, Kuwait.
6 Department of Pediatrics, Al-Adan Hospital, Kuwait, Kuwait.
7 The Royal Hospital, Muscat, Oman.
8 GeneDx, Gaithersburg, MD, USA.
9 Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar. email@example.com.
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MICU1 encodes a Ca2+ sensing, regulatory subunit of the mitochondrial uniporter, a selective calcium channel within the organelle’s inner membrane. Ca2+ entry into mitochondria helps to buffer cytosolic Ca2+transients and also activates ATP production within the organelle. Mutations in MICU1 have previously been reported in 17 children from nine families with muscle weakness, fatigue, normal lactate, and persistently elevated creatine kinase, as well as variable features that include progressive extrapyramidal signs, learning disabilities, nystagmus, and cataracts. In this study, we report the clinical features of an additional 13 patients from consanguineous Middle Eastern families with recessive mutations in MICU1. Of these patients, 12/13 are homozygous for a novel founder mutation c.553C>T (p.Q185*) that is predicted to lead to a complete loss of function of MICU1, while one patient is compound heterozygous for this mutation and an intragenic duplication of exons 9 and 10. The founder mutation occurs with a minor allele frequency of 1:60,000 in the ExAC database, but in ~1:500 individual in the Middle East. All 13 of these patients presented with developmental delay, learning disability, muscle weakness and easy fatigability, and failure to thrive, as well as additional variable features we tabulate. Consistent with previous cases, all of these patients had persistently elevated serum creatine kinase with normal lactate levels, but they also exhibited elevated transaminase enzymes. Our work helps to better define the clinical sequelae of MICU1 deficiency. Furthermore, our work suggests that targeted analysis of the MICU1 founder mutation in Middle Eastern patients may be warranted.