Mutations in genes encoding mitochondrial proteins are increasingly recognized as a major cause of neurodegenerative disorders, owing to the role of mitochondria in neuronal energy metabolism and signaling. Here, we investigate MTNAP1 (mitochondrial nucleoid-associated protein 1) as a novel gene associated with an autosomal recessive neurodevelopmental disorder characterized by progressive cerebral and cerebellar atrophy. Three affected probands from two unrelated families presented with global developmental delay, ataxia, spasticity, seizures, and progressive neurological decline, with MRI revealing generalized cerebral and cerebellar volume loss and thinning of the corpus callosum. Trio-based exome sequencing uncovered two ultra-rare, biallelic loss-of-function variants in MTNAP1: a homozygous missense variant (p.G553R) in two siblings and a homozygous nonsense variant (p.Y13X) in an unrelated proband. Functional studies in proband-derived fibroblasts and MTNAP1-silenced neuronal cells implicated profound mitochondrial fragmentation, reduced oxidative phosphorylation capacity, increased reactive oxygen species accumulation, and premature senescence-like stress responses. Structural modeling and biophysical analyses revealed that the p.G553R variant destabilizes the MTNAP1 fold, disrupts its DNA- and membrane-binding interfaces, and induces aberrant aggregation, leading to loss of mitochondrial integrity. Collectively, our findings suggest MTNAP1 as a crucial regulator of mitochondrial homeostasis and identify pathogenic MTNAP1 variants as the cause of a novel, progressive neurodegenerative disorder.
Kumar et al. (2026) studied this question.