MTPAP – Mitochondrial Disease

Autosomal recessive biallelic variants in MTPAP have been reported in a patient with a mitochondrial multisystem disorder characterized by sensory and motor axonal polyneuropathy. Whole-exome sequencing in a Japanese cohort of 247 patients with suspected hereditary neuropathy identified one unrelated proband with compound heterozygous MTPAP variants, c.833G>T (p.Arg278Ile) and c.1531C>T (p.Gln511Ter) (PMID:35235001). The case lacked extended segregation data but demonstrated concordant clinical features of central nervous system involvement and mild muscle neurogenic changes without overt mitochondrial histopathology.

Functional studies of the p.Asn478Asp mutation in patient fibroblasts revealed loss of polyadenylation of all mitochondrial transcripts, severe deficiency of oxidative phosphorylation complexes I and IV, and impaired mitochondrial protein synthesis; these defects were rescued by overexpression of wild-type mtPAP (PMID:25008111). In vitro assays confirmed compromised polymerase activity of the mutant enzyme, establishing haploinsufficiency of mtPAP as a pathogenic mechanism.

Key Take-home: MTPAP should be included in gene panels for patients presenting with complex axonal polyneuropathy and suspected mitochondrial disease.

References

• Journal unavailable | Year unavailable | Title unavailable PMID:35235001
• Human Molecular Genetics | 2014 | A human mitochondrial poly(A) polymerase mutation reveals the complexities of post-transcriptional mitochondrial gene expression. PMID:25008111

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