C19orf12 – Neurodegeneration with Brain Iron Accumulation

C19orf12 encodes a mitochondrial membrane protein whose biallelic variants cause autosomal recessive neurodegeneration with brain iron accumulation (NBIA) (MPAN subtype). This disorder is characterized by progressive extrapyramidal and pyramidal signs, cognitive decline, optic atrophy, and motor axonal neuropathy, often with iron deposition in globus pallidus and substantia nigra on MRI.

Genetic evidence supports a strong gene–disease association. Over 67 MPAN cases with confirmed biallelic C19orf12 variants have been reported (PMID:24209434), including missense, frameshift, and splice‐altering alleles. A recurrent founder allele, c.-2C>T (p.Thr11Met), was identified in 9 Turkish probands and co-segregated in 16 affected relatives (PMID:28347615). Other loss-of-function variants and missense mutations cluster within a conserved hydrophobic domain, underscoring their pathogenicity.

Inheritance is autosomal recessive. Segregation analysis in multiple consanguineous families revealed homozygosity of pathogenic alleles in 16 additional affected relatives (PMID:28347615). A representative variant reported in early NBIA cases is c.187G>C (p.Ala63Pro) (PMID:23857908).

The phenotypic spectrum ranges from childhood onset with spastic paraplegia and optic atrophy to variable adult-onset presentations featuring dystonia, parkinsonism, psychiatric manifestations, and cognitive impairment. Key HPO‐mapped features include HP:0001332 (Dystonia), HP:0001300 (Parkinsonism), HP:0007256 (Abnormal pyramidal sign), HP:0000648 (Optic atrophy), and HP:0007002 (Motor axonal neuropathy).

Functional studies demonstrate that C19orf12 variants disrupt subcellular localization, impair oxidative stress response, and increase mitochondrial calcium load and apoptosis in patient fibroblasts (PMID:26136767). Knock-down of Drosophila orthologs recapitulates neurodegeneration and bang sensitivity, supporting a loss‐of‐function mechanism (PMID:24586779).

Integration of genetic segregation, variant spectrum, and concordant functional data yields a Strong ClinGen classification. C19orf12 sequencing should be included in genetic panels for NBIA and related motor neuron‐like presentations. Early molecular diagnosis enables informed genetic counseling and consideration of iron‐modulating therapies.

References

• 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
• Frontiers in genetics • 2015 • Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization ... PMID:26136767
• PLoS One • 2014 • Impairment of Drosophila orthologs of the human orphan protein C19orf12 induces bang sensitivity and neurodegeneration. PMID:24586779

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