AGPAT2 – AGPAT2-related Congenital Generalized Lipodystrophy

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive syndrome characterized by near-total loss of adipose tissue from birth and severe metabolic complications. The AGPAT2 gene encodes 1-acylglycerol-3-phosphate O-acyltransferase 2, a key enzyme in triglyceride and phospholipid biosynthesis. Loss-of-function variants in AGPAT2 underlie CGL type 1, impairing adipocyte differentiation and lipid storage. This summary synthesizes genetic and experimental evidence linking AGPAT2 to congenital generalized lipodystrophy.

Large family-based and cohort studies have established a strong gene-disease relationship. In a multi-ethnic linkage analysis of 20 affected individuals from 11 pedigrees, AGPAT2 mutations segregated recessively with the CGL phenotype (PMID:11967537). Subsequent screening identified AGPAT2 variants in 38 patients from 30 families with classic lipodystrophy features, accounting for the majority of CGL1 cases (PMID:12765973). Segregation across multiple unrelated families confirms autosomal recessive inheritance and high penetrance of AGPAT2 alleles.

The variant spectrum includes frameshift, nonsense, splice-site, and missense mutations. Loss-of-function alleles such as c.259C>T (p.Gln87Ter) result in truncated AGPAT2 and undetectable enzyme activity in homozygous carriers. Multiple private and recurrent variants (e.g., p.Ala239Val, c.369_372del) have been reported across diverse populations, supporting genetic heterogeneity yet a consistent mechanistic impact.

Functional assays demonstrate that AGPAT2 deficiency reduces enzymatic conversion of lysophosphatidic acid to phosphatidic acid. Mutants including R68X, D180fs, and p.Leu228Pro exhibit <15% residual activity, while some missense alleles retain partial function (PMID:15629135). Cellular studies in AGPAT2-deficient preadipocytes reveal impaired adipogenesis, increased apoptosis after differentiation induction, and altered lipid signaling pathways, effects partially rescued by re-expression of wild-type AGPAT2 (PMID:22872237).

No significant conflicting evidence has emerged; BSCL2 and other genes explain CGL type 2 and rarer subtypes, but AGPAT2 variation remains the exclusive driver of type 1 disease.

Integration of genetic segregation, variant pathogenicity, and concordant functional data supports a Strong ClinGen classification for AGPAT2–CGL association. AGPAT2 genetic testing is clinically actionable, guiding diagnosis, carrier screening, and targeted metabolic management in CGL patients.

References

• Nature Genetics • 2002 • AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. PMID:11967537
• Diabetes • 2003 • Prevalence of mutations in AGPAT2 among human lipodystrophies. PMID:12765973
• Biochemical and Biophysical Research Communications • 2005 • Enzymatic activity of naturally occurring 1-acylglycerol-3-phosphate-O-acyltransferase 2 mutants associated with congenital generalized lipodystrophy. PMID:15629135
• Diabetes • 2012 • Alterations in lipid signaling underlie lipodystrophy secondary to AGPAT2 mutations. PMID:22872237

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