C19orf12 – Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN)

Mitochondrial membrane protein-associated neurodegeneration (MPAN, NBIA4) is a rare autosomal recessive neurodegenerative disorder characterized by progressive dystonia, parkinsonism, pyramidal signs, optic atrophy, and motor axonal neuropathy due to iron accumulation predominantly in the globus pallidus and substantia nigra ([PMID:24636776]). MPAN accounts for up to 30% of NBIA cases and typically presents in childhood or early adulthood, although late‐onset and atypical forms have been reported ([PMID:24209434]).

Genetic studies have identified biallelic loss‐of‐function and missense variants in C19orf12 in over 100 unrelated probands ([PMID:24209434]), with multi‐family segregation of homozygous p.Thr11Met in 16 affected relatives from Turkish founder pedigrees ([PMID:28347615]). Additionally, autosomal dominant MPAN has been demonstrated by segregation of monoallelic truncating variants in eight patients across two large families, supporting a dominant‐negative mechanism ([PMID:31087512]).

The C19orf12 variant spectrum includes missense changes (e.g., c.172G>A (p.Gly58Arg)), frameshifts (e.g., c.204_214del (p.Gln69GlyfsTer18)), splice‐site mutations (e.g., c.193+5>A), and multi‐exon deletions. Founder mutations such as p.Thr11Met recur in specific populations, and de novo frameshift alleles (e.g., c.336_338delinsCACA (p.Trp112CysfsTer40)) extend the inheritance model to autosomal dominant PMAN presentations ([PMID:30088953]; [PMID:31087512]).

Functional assays demonstrate that pathogenic C19orf12 variants disrupt mitochondrial and endoplasmic reticulum localization, impair oxidative stress–induced relocalization, elevate mitochondrial calcium, and promote apoptosis in patient fibroblasts ([PMID:26136767]). Fibroblast studies further reveal altered iron storage metabolism and autophagy defects in autosomal dominant MPAN compared to recessive cases ([PMID:37605305]).

Integration of genetic and functional evidence establishes a definitive gene-disease relationship. The robust segregation data, consistent phenotypic spectrum across >100 cases, and concordant cellular phenotypes support definitive clinical validity. Key Take-home: C19orf12 genetic testing is indicated for individuals with NBIA4 features, and functional assays may inform pathogenicity assessments and therapeutic strategies.

References

• Neurologia i neurochirurgia polska • 2014 • Mitochondrial protein associated neurodegeneration - case report. PMID:24636776
• International review of neurobiology • 2013 • Mitochondrial membrane protein-associated neurodegeneration (MPAN). PMID:24209434
• Parkinsonism & related disorders • 2017 • The p.Thr11Met mutation in c19orf12 is frequent among adult Turkish patients with MPAN. PMID:28347615
• Molecular genetics & genomic medicine • 2019 • Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN). PMID:31087512
• Neurocase • 2018 • Mitochondrial membrane protein-associated neurodegeneration: a case report and literature review. PMID:30088953
• Frontiers in genetics • 2015 • Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca²⁺. PMID:26136767
• Movement disorders • 2023 • Autosomal Dominant MPAN: Mosaicism Expands the Clinical Spectrum to Atypical Late-Onset Phenotypes. PMID:37605305

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