LIPE – LIPE‐related Familial Partial Lipodystrophy (FPLD6)

Familial partial lipodystrophy type 6 (FPLD6) is a rare autosomal recessive disorder characterized by loss of subcutaneous adipose tissue and severe metabolic complications. A single Chinese proband presented at age 20 with hypertriglyceridemia, diabetes mellitus, hepatic steatosis, hepatomegaly, retinal changes, peripheral neuropathy and renal tubular injury due to compound heterozygous LIPE frameshift variants c.2497_2501del (p.Glu833LysfsTer22) and c.2705del (p.Ser902ThrfsTer27) inherited from each parent (PMID:39113684). These two loss‐of‐function alleles disrupt hormone‐sensitive lipase (HSL) activity, consistent with a loss‐of‐function mechanism. HSL is critical for adipocyte lipolysis, and in vitro studies of HSL phosphorylation and activation at Ser649/Ser650 support the necessity of intact enzyme function for lipid mobilization (PMID:19018281). No additional affected relatives were reported, and no other families have been described. Together these data meet criteria for a Limited ClinGen clinical validity classification. Genetic testing for LIPE variants is indicated in early‐onset lipodystrophy with metabolic syndrome to guide diagnosis and management.

References

• Frontiers in genetics • 2024 • Case report: First Chinese patient with family partial lipodystrophy type 6 due to novel compound heterozygous mutations in the LIPE gene. PMID:39113684
• PloS one • 2008 • Ser649 and Ser650 are the major determinants of protein kinase A-mediated activation of human hormone-sensitive lipase against lipid substrates. PMID:19018281

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