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ATPases Associated with Diverse Cellular Activities
Female
*Homozygote
Humans
Male
Metalloendopeptidases/*genetics
Mitochondria/*pathology
Mitochondrial Diseases/*genetics
Mitochondrial Proteins
*Mutation, Missense
Optic Atrophy/*genetics
*opa1
*yme1l1
*human
*human biology
*intellectual disability
*medicine
*mitochondrial fragmentation
*mitochondriopathy
*mouse
*optic atrophy
Abstract:
Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans.
