A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients
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.
KeywordsArabs Creatine kinase Learning disability Liver transaminases MICU1 Mitochondrial disorders
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Conflict of Interest
Sara Musa, Vamsi K. Mootha, Wafaa Eyaid, Rehab Ali, Mariam Al-Mureikhi, Nawal Makhseed, Zakkiriah Mohamed, Wafaa Ali AlShehhi, Kimberli J. Kamer, Jane Juusola, Fatma Al Mesaifri, Noora Shahbeck, and Tawfeg Ben-Omran declare that they have no conflict of interest.
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 (5). Informed consent was obtained from all patients for being included in the study.
Sara Musa and Tawfeg Ben Omran designed the study and drafted the first article.
Sara Musa, Jane Juusola, and Tawfeg Ben Omran performed data analysis and interpretation.
Sara Musa, Vamsi Mootha, Rehab Ali, Mariam al-mureikhi, Wafaa Eyaid, Wafaa Shehhi, Nawal Makhseed, Zakkariah Mohamed, Kimberli J. Kamer, Fatma Al Mesaifri, Noora Shahbeck, and Tawfeg Ben Omran collected the data, performed critical review of the final manuscript, and approved the final version of the manuscript.
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