pp 1-5 | Cite as
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
Compliance with Ethics Guidelines
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.
- Csordas G, Golenar T, Seifert EL, Kamer KJ, Sancak Y, Perocchi F, Moffat C, Weaver D, de la Fuente Perez S, Bogorad R, Koteliansky V, Adijanto J, Mootha VK, Hajnoczky G (2013) MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter. Cell Metab 17:976–987Google Scholar
- Kamer KJ, Mootha VK (2014) MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter. EMBO Rep 15:299–307Google Scholar
- Kamer KJ, Mootha VK (2015) The molecular era of the mitochondrial calcium uniporter. Nat Rev Mol Cell Biol 16:545–553Google Scholar
- Kamer KJ, Grabarek Z, Mootha VK (2017) High-affinity cooperative Ca2+ binding by MICU1-MICU2 serves as an on-off switch for the uniporter. EMBO Rep 18:1397–1411Google Scholar
- Lek M, Karczewski K, Minikel E, Samocha K, Banks E, Fennell T, O’Donnell-Luria A, Ware J, Hill A, Cummings B, Tukiainen T, Birnbaum D, Kosmicki J, Duncan L, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Cooper D, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki M, Levy Moonshine A et al (2015) Analysis of protein-coding genetic variation in 60,706 humans. bioRxiv. https://doi.org/10.1101/030338
- Lewis-Smith D, Kamer KJ, Griffin H, Childs AM, Pysden K, Titov D, Duff J, Pyle A, Taylor RW, Yu-Wai-Man P, Ramesh V, Horvath R, Mootha VK, Chinnery PF (2016) Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood. Neurol Genet 2:e59Google Scholar
- Logan CV, Szabadkai G, Sharpe JA, Parry DA, Torelli S, Childs AM, Kriek M, Phadke R, Johnson CA, Roberts NY, Bonthron DT, Pysden KA, Whyte T, Munteanu I, Foley AR, Wheway G, Szymanska K, Natarajan S, Abdelhamed ZA, Morgan JE, Roper H, Santen GW, Niks EH, van der Pol WL, Lindhout D, Raffaello A, De Stefani D, den Dunnen JT, Sun Y, Ginjaar I et al (2013) Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nat Genet 46:188–193Google Scholar
- Mallilankaraman K, Doonan P, Cardenas C, Chandramoorthy HC, Muller M, Miller R, Hoffman NE, Gandhirajan RK, Molgo J, Birnbaum MJ, Rothberg BS, Mak D-OD, Foskett JK, Madesh M (2012) MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell 151:630–644Google Scholar
- Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE, Palmer AE, Mootha VK (2010) MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature 467:291–296Google Scholar
- Yavarna T, Al-Dewik N, Al-Mureikhi M, Ali R, Al-Messaifri F, Mahmoud L, Shahbeck N, Lakhani S, Al Mulla M, Nawaz Z, Vitazka P, Alkuraya FS, Ben-Omran T (2015) High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mandelian disorders. Hum Genet 134(9):967–980Google Scholar