Mutations in @entity44172 , Encoding a Complex I Component of the Mitochondrial Respiratory Chain, Cause XXXX with Linear Skin Defects Syndrome.

@entity2125 @entity32489 @entity44172 @entity12931 @entity8211 @entity4353 @entity5462 @entity1112 @entity46622 @entity74 @entity299 @entity3894 @entity2383
UNASSIGNED: @entity32489 ( @entity32489 ) syndrome is an @entity1112 also known as MIDAS ( @entity4353 , dermal @entity3894 , and @entity46622 ). Additional clinical features include neurological and @entity299 . @entity32489 is genetically heterogeneous given that heterozygous mutations in @entity5462 or @entity8211 have been identified in @entity32489 -affected females. Both genes encode proteins involved in the structure and function of complexes III and IV, which form the terminal segment of the mitochondrial respiratory chain (MRC). However, not all individuals with @entity32489 carry a mutation in either @entity5462 or @entity8211 . The majority of @entity32489 -affected females have severe skewing of X chromosome inactivation, suggesting that mutations in @entity5462 , @entity8211 , and other as-yet-unidentified X-linked gene(s) cause selective loss of cells in which the mutated X chromosome is active. By applying whole-exome sequencing and filtering for X-chromosomal variants, we identified a de novo nonsense mutation in @entity44172 (Xp11.23) in one female individual and a heterozygous 1-bp deletion in a second individual, her asymptomatic mother, and an affected aborted fetus of the subject's mother. @entity44172 encodes one of 30 poorly characterized supernumerary subunits of @entity2125 : @entity12931 oxidoreductase, known as complex I (cI), the first and largest enzyme of the MRC. By shRNA-mediated @entity44172 knockdown in HeLa cells, we demonstrate that @entity44172 is essential for cI assembly and activity as well as cell growth and survival. These results demonstrate that @entity74 leading to the complete inactivation of complex I, III, or IV underlie @entity32489 . Our data reveal an unexpected role of cI dysfunction in a developmental phenotype, further underscoring the existence of a group of @entity2383 associated with neurocutaneous manifestations.
