{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:14:17Z","timestamp":1783037657054,"version":"3.54.6"},"reference-count":27,"publisher":"Cold Spring Harbor Laboratory","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cold Spring Harb Mol Case Stud"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:p>Variants in the X-linked gene <jats:italic>AIFM1<\/jats:italic> (apoptosis-inducing factor mitochondria-associated 1) are associated with a highly variable clinical presentation that encompasses motor neuropathy, ataxia, encephalopathies, deafness, and cognitive impairment. <jats:italic>AIFM1<\/jats:italic> encodes a mitochondrial flavin adenine dinucleotide (FAD)-dependent nicotinamide adenine dinucleotide (NADH) oxidoreductase, with roles in the regulation of respiratory complex assembly and function, production of reactive oxygen species, and the coordination of a caspase-independent type of apoptosis known as parthanatos. In this report, we describe a missense <jats:italic>AIFM1<\/jats:italic> variant (absent in reference population databases; c.506C &gt; T, p.Pro169Leu) identified in the proband and sibling of a family with three affected males. The proband, his brother, and their maternal uncle all exhibited severe multisystem pathology, metabolic acidosis, and early demise. Metabolic testing on the proband revealed normal activity of the pyruvate dehydrogenase complex in skin fibroblasts. Absent or partial deficiency of cytochrome <jats:italic>c<\/jats:italic> oxidase was found in muscle fibers, however, supporting a Complex IV mitochondrial deficiency. Functional studies carried out on fibroblasts from the proband demonstrated reduced steady state levels of the AIFM1 protein, decreased Complex I subunit abundance, elevated sensitivity to the apoptosis inducer staurosporine, and increased nuclear condensation when grown in galactose-containing media. The reduced abundance of AIFM1 in the patient cells could not be stabilized with riboflavin or protease inhibitor treatment. Together, these findings suggest that the normal function of the <jats:italic>AIFM1<\/jats:italic> gene product within mitochondria, and its response to apoptotic stimuli, are impaired by this variant, likely accounting for the severity of the phenotype seen in these patients. These findings also imply tissue-specific effects of this variant on different mitochondrial complexes. This study expands the genetic and phenotypic spectrum associated with <jats:italic>AIFM1<\/jats:italic> variants, with the combination of exome sequencing and functional studies allowing a diagnosis to finally be confirmed for this family.<\/jats:p>","DOI":"10.1101\/mcs.a006081","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T21:20:26Z","timestamp":1623446426000},"page":"a006081","source":"Crossref","is-referenced-by-count":13,"title":["Severe multisystem pathology, metabolic acidosis, mitochondrial dysfunction, and early death associated with an X-linked <i>AIFM1<\/i> 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