The relationship between MICU1 and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 20, 2023. MICU1 encodes mitochondrial calcium uptake protein 1. This is a key regulator of the mitochondrial calcium uniporter (MCU), a multi-subunit calcium channel of the mitochondrial inner membrane. MICU1 senses calcium levels via its EF-hand domains.
MICU1 was first reported in relation to autosomal recessive primary mitochondrial disease in 2014 (PMID: 24336167). While various names have been given to the constellation of features seen in those with MICU1-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the MICU1 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.
Evidence supporting the relationship between MICU1 and autosomal recessive primary mitochondrial disease includes case-level data and experimental data. This curation included two nonsense variants and two splicing / frameshift variants resulting in truncation observed in four probands in three publications (PMIDs: 24336167, 29721912, 33969448). All cases included in this curation were homozygous for the variant, and parents were confirmed carriers. There are additional cases reported in the medical literature (PMIDs: 33428302, 32395406, 36425804, 27123478), including individuals with exonic level deletions, however these were not included in this curation as the maximum genetic evidence score was reached. Age of onset is typically in early childhood but can also be seen up to adulthood. Clinical features in affected individuals include myopathy, developmental delay, ataxia, extrapyramidal signs, chorea, tremor, dystonia, microcephaly, neuropathy, optic atrophy, and ophthalmoplegia.
The mechanism of disease is loss of function. This gene-disease association is also supported by a expression in brain and muscle, and several mouse models showing the impact of MICU1 knockout on mitochondrial calcium uptake (PMIDs: 24336167, 27477272, 35302860).
In summary, there is definitive evidence to support the relationship between MICU1 and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 20, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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