MICU2

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MICU2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 19, 2023. *MICU2* encodes mitochondrial calcium uptake protein 2. This is a subunit of the mitochondrial uniporter complex, a multi-subunit calcium channel of the mitochondrial inner membrane. *MICU2* is involved in calcium import into the mitochondrion and negative regulation of mitochondrial calcium ion concentration by regulating calcium channel opening. The *MICU2* gene has been reported in relation to autosomal recessive primary mitochondrial disease in one case to date in 2017 (PMID: 29053821). This was an 11-year-old girl with cognitive delay and intellectual disability. Brain MRI showed gliosis and T2 hyperintense foci in both cerebral hemisphere in a subcortical distribution. She had a similarly affected brother who also had abnormal eye movements. Although the phenotype is nonspecific, there was a homozygous nonsense variant in *MICU2* present in these two siblings, and given the calcium flux abnormalities noted in patient cells, this GCEP elected to include this family in this curation. While various names could be given to the constellation of features seen in those with *MICU2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MICU2* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. As described above, this curation includes one proband with a homozygous nonsense variant from one publication (PMID: 29053821). This gene-disease association is also supported by the known biochemical function of *MICU2* that is shared with *MICU1*, a gene with a definitive association to primary mitochondrial disease (PMID: 26903221). It is also supported by experimental data including mitochondrial calcium uptake studies with either shRNA or siRNA knockdown in HeLa cells (PMIDs: 26903221, 24560927) and knockout mice (PMID: 29073106). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 19, 2023 (SOP Version 9).