AGA and Aspartylglucosaminuria

Aspartylglucosaminuria is a lysosomal storage disorder caused by mutations in the AGA gene (HGNC:318), resulting in deficient activity of the lysosomal enzyme aspartylglucosaminidase. Multiple case reports from diverse ethnic groups, including Finnish, Japanese, Palestinian, and Caucasian populations, consistently document autosomal recessive inheritance with compound heterozygous and homozygous mutations (PMID:15365992, PMID:28063748). This pervasive evidence forms the basis for strong clinical confidence in the gene–disease association.

Genetic evidence comes from comprehensive case studies revealing a spectrum of variant types such as missense, splice, and frameshift mutations. For example, a Finnish patient was identified as a compound heterozygote carrying the well‐characterized Finnish major allele and a rarer point mutation (PMID:15365992), while other reports describe novel homozygous mutations identified via exome sequencing (PMID:28063748). In several families, additional affected relatives show co‐segregation of these pathogenic mutations, reinforcing autosomal recessive inheritance through extended family analyses (PMID:9627765).

The variant spectrum includes numerous alterations, with a representative mutation being c.44T>G (p.Leu15Arg). This specific variant, along with others detected in multiple unrelated probands, implicates critical regions of the gene that disrupt protein translocation and processing. In the reported cases, such variants result in either reduced enzyme quantity or severe mislocalization, correlating with the progressive neurodevelopmental and systemic manifestations of the disease.

Further genetic delineation shows that affected patients harbor variants across distinct domains of the AGA gene. The aggregate data from over 30 probands (PMID:23271757) and several multi‐patient studies provide robust segregation data and emphasize the impact of both recurrent and private mutations in eliciting the disease phenotype. These findings have been instrumental in establishing sensitive molecular diagnostic assays and in guiding carrier screening efforts.

Complementary functional studies have elucidated the pathophysiological basis of aspartylglucosaminuria. In vitro mutagenesis and cellular assays consistently demonstrate that mutations impair autocatalytic activation of the AGA precursor and disrupt normal lysosomal targeting. Although rescue studies using compounds such as Amlexanox have shown promising increases in enzyme activity in vitro (PMID:29247835), the variability of experimental systems has led to a moderate rating for functional evidence despite clear concordance with the human phenotype.

In summary, the integration of comprehensive genetic data with corroborative functional assays provides strong evidence for the association between AGA mutations and aspartylglucosaminuria. This robust body of literature supports its implementation in diagnostics, therapeutic development, and commercial genetic testing, ultimately ensuring that affected individuals can benefit from targeted interventions.

References

• Human Mutation • 2004 • A novel aspartylglucosaminuria mutation affects translocation of aspartylglucosaminidase PMID:15365992
• Human Mutation • 1995 • Identification of a novel mutation causing aspartylglucosaminuria reveals a mutation hotspot region in the aspartylglucosaminidase gene PMID:7627186
• Biochimica et Biophysica Acta. Molecular Basis of Disease • 2018 • Amlexanox provides a potential therapy for nonsense mutations in the lysosomal storage disorder Aspartylglucosaminuria PMID:29247835

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