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POLG encodes the catalytic subunit of mitochondrial DNA polymerase γ, essential for mtDNA replication and repair. Pathogenic variants in POLG cause a spectrum of mitochondrial disorders including progressive external ophthalmoplegia, Alpers syndrome, and recessive mitochondrial ataxia syndrome (MIRAS). MIRAS manifests as juvenile- or adult-onset cerebellar ataxia, often accompanied by peripheral neuropathy, dysarthria, seizures, and involuntary movements. The disease follows an autosomal recessive inheritance pattern. Diagnosis is frequently delayed due to phenotypic overlap with spinocerebellar ataxias of dominant inheritance. Here, we review the evidence linking POLG recessive variants to MIRAS (POLG, mitochondrial recessive ataxia syndrome).
A case report described a mother and her son both homozygous for the c.2243G>C (p.Trp748Ser) POLG variant, presenting with progressive ataxia and SCA-like anticipation (PMID:22166854). Muscle histology and mitochondrial DNA analyses confirmed features consistent with mitochondrial recessive ataxia syndrome. Although the pedigree mimicked dominant spinocerebellar ataxia, both affected individuals were homozygous while the healthy father was a heterozygous carrier. The presence of two independent mutant alleles within the family highlighted the high carrier frequency and risk of recessive disease in consanguineous or genetically isolated populations. This report underscored the need to consider MIRAS in dominantly inherited ataxia cases of unknown etiology. It also demonstrated clear segregation of the homozygous variant with disease in one multiplex family.
In a Finnish cohort, 27 patients from 15 unrelated families were homozygous for the W748S+E1143G POLG allele pair, defining a common cause of MIRAS in northern Europe (PMID:16080118). Haplotype analysis of these and 13 non-Finnish European patients revealed that all disease chromosomes carrying W748S+E1143G trace back to a single ancient European founder. The carrier frequency in the Finnish population was estimated at 1 : 125. Despite identical genotype, patients exhibited phenotypic heterogeneity ranging from adult- to juvenile-onset ataxia with variable peripheral neuropathy, dysarthria, cognitive impairment, involuntary movements, psychiatric symptoms, and seizures. This phenotypic spectrum underscores variable expressivity even with the same POLG genotype. The founder haplotype and high population prevalence support substantial genetic evidence for an AR association with MIRAS.
The recessive variant spectrum in MIRAS is dominated by missense changes such as p.Trp748Ser and p.Glu1143Gly, most often occurring in cis as a haplotype. Additional hypomorphic alleles, notably p.Ala467Thr, also contribute as compound heterozygotes in combination with p.Trp748Ser or other pathogenic variants. While p.Trp748Ser alone is insufficient for disease, its cis occurrence with p.Glu1143Gly or trans occurrence with p.Ala467Thr leads to mtDNA replication defects. The genetic evidence includes 29 probands across 16 families, fulfilling AR segregation criteria and reaching the ClinGen genetic evidence cap. No alternative phenotypes have been consistently associated with these recessive variants. The inheritance pattern, segregation data, and recurrent founder alleles establish a strong AR genetic association.
Functional studies of the p.Ala467Thr variant demonstrate that it retains only 4% of wild-type polymerase activity and fails to interact effectively with the accessory p55 subunit, reducing processivity (PMID:16024923). These hypomorphic effects on catalytic efficiency mirror the recessive ataxia phenotype observed in MIRAS. While direct biochemical analysis of p.Trp748Ser remains limited, the severe reduction of enzymatic function by common MIRAS alleles supports a loss-of-function mechanism. The ancient founder haplotype for W748S+E1143G also implies preserved functional domains disrupted by pathogenic missense changes. Cellular and animal model data, including yeast complementation assays, further corroborate mutational impact on mtDNA maintenance. We designate the functional evidence tier as Moderate.
Collectively, extensive genetic and functional data affirm that recessive POLG variants, particularly p.Trp748Ser in cis with p.Glu1143Gly or in trans with p.Ala467Thr, constitute a common molecular basis for MIRAS of variable onset. Genetic testing including analysis for these founder alleles should be prioritized in undiagnosed progressive ataxia, even in pedigrees suggestive of dominant inheritance. The strong AR association and mechanistic evidence justify inclusion of POLG in clinical gene panels for mitochondrial and ataxia syndromes. Further studies may refine genotype-phenotype correlations and explore additional modifiers. Key take-home: screening for c.2243G>C (p.Trp748Ser) and c.1399G>A (p.Ala467Thr) enables early diagnosis and management of MIRAS, improving patient care and genetic counseling.
Gene–Disease AssociationStrong29 probands (including 27 from 15 Finnish families [PMID:16080118] and 2 in a multiplex family [PMID:22166854]); consistent segregation in 16 families; functional concordance Genetic EvidenceStrong29 probands across 16 families with recessive POLG variants; AR segregation meets genetic evidence criteria Functional EvidenceModerateA467T and W748S variants show severe reduction in polymerase activity [PMID:16024923] and founder haplotype studies indicate ancient European origin |