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Angiogenin (ANG) is a secreted ribonuclease whose heterozygous missense variants have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disorder affecting upper and lower motor neurons. The gene–disease relationship follows an autosomal dominant pattern with reduced penetrance, and no consistent segregation has been observed in multigenerational pedigrees (affected_relatives=0). Multiple independent cohorts have identified ANG variants in apparently sporadic ALS patients, supporting a contributory role in disease risk.
Genetic screening across diverse populations has uncovered at least 24 unrelated probands carrying rare ANG missense mutations: 15 individuals in an initial report (PMID:16501576), 9 carriers in an Italian series (PMID:18087731), and additional cases in French (PMID:18852347), German (PMID:19363631), and Hungarian cohorts (PMID:31025543). The recurrent c.122A>T (p.Lys41Ile) variant has been observed across multiple studies, and population frequencies remain below 0.5% in controls, consistent with a pathogenic spectrum of rare missense changes.
Functional assays have demonstrated that ALS-associated ANG variants uniformly exhibit loss of either ribonucleolytic or nuclear translocation activity, or both. Site-directed mutants corresponding to patient alleles (e.g., p.Ile70Val, p.Lys41Ile) show markedly reduced ribonuclease cleavage of tRNA substrates and impaired nuclear localization in neuronal cells (PMID:17886298; PMID:17900154). In vitro and cellular studies further reveal that wild-type ANG promotes motor neuron survival via PI3K/Akt signaling, whereas ALS-linked mutants fail to rescue excitotoxic or ER stress–induced death (PMID:19109488). In vivo, ANG delivery extends lifespan and preserves motor neurons in SOD1^G93A transgenic mice, confirming functional relevance to ALS pathogenesis.
No large pedigrees with definitive segregation have been reported, and some variants show incomplete penetrance. Meta-analyses indicate that ANG variants confer moderate risk for ALS but are rare overall (PMID:26255299). There is no evidence for common founder effects beyond isolated haplotypes, and oligogenic interactions with other ALS genes may modulate penetrance.
Integration of genetic and mechanistic data supports a definitive gene–disease association: ANG missense mutations impair enzymatic and nuclear functions critical for motor neuron viability, and their heterozygous occurrence in >24 unrelated ALS cases across multiple populations meets ClinGen criteria for strong clinical validity. Routine screening of ANG in ALS patients informs genetic counseling and may identify candidates for experimental therapies targeting ANG-mediated pathways.
Key Take-home: Heterozygous ANG missense variants cause loss of ribonucleolytic and nuclear functions, contributing to ALS risk and warranting inclusion in diagnostic gene panels.
Gene–Disease AssociationStrong24 unrelated probands with heterozygous ANG missense variants across multiple cohorts and concordant functional loss Genetic EvidenceModerate24 probands in five independent populations; rare recurrent variant c.122A>T (p.Lys41Ile) Functional EvidenceStrongIn vitro and in vivo assays demonstrate loss of ribonucleolytic/nuclear translocation activity and motor neuron rescue only by wild-type ANG |