CAVIN1 – Congenital Generalized Lipodystrophy Type 4

Congenital generalized lipodystrophy type 4 (CGL4) is an autosomal recessive disorder caused by biallelic variants in CAVIN1 (also known as PTRF), a gene encoding cavin-1, a master regulator of caveolae biogenesis essential for adipocyte function and muscle integrity ([PMID:19726876]).

To date, 18 unrelated probands have been reported with CGL4 due to CAVIN1 mutations ([PMID:24024685]). In one consanguineous family, two siblings co-segregated a homozygous PTRF mutation with disease, confirming inheritance in an autosomal recessive pattern ([PMID:37501786]).

The allelic spectrum is dominated by loss-of-function variants, including frameshift and nonsense changes such as c.259C>T (p.Gln87Ter) ([PMID:27167729]), and at least one pathogenic missense variant, p.Asp59Val, demonstrating both complete and partial protein‐disrupting mechanisms ([PMID:27144934]).

Functional studies in patient fibroblasts and murine 3T3-F442A preadipocytes show cavin-1 deficiency leads to loss of caveolae, secondary deficiency of caveolin-1/-2, increased autophagic flux, impaired adipocyte differentiation, and blunted insulin signaling, all of which are rescued by ATG5 silencing ([PMID:27144934]). Overexpression constructs of human PTRF mutations in myoblasts mislocalize PTRF and disrupt caveolin interactions, recapitulating muscular dystrophy and lipodystrophy phenotypes ([PMID:19726876]).

Clinically, patients present with generalized near-total absence of subcutaneous fat (lipoatrophy), muscular dystrophy/rippling myopathy, hyperCKemia, insulin resistance, hypertriglyceridemia, hepatomegaly, ventricular arrhythmias, gastrointestinal dysmotility, and atlantoaxial instability, reflecting the multisystem role of caveolae in lipid and muscle homeostasis.

Collectively, the robust genetic and experimental concordance supports a Strong ClinGen gene–disease validity classification for CAVIN1 in CGL4. Early molecular diagnosis enables targeted surveillance for metabolic and cardiac complications and guides therapeutic interventions such as metreleptin or triglyceride-lowering agents.

References

• The Journal of Clinical Investigation • 2009 • Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy [PMID:19726876]
• BMC Medical Genetics • 2013 • Novel PTRF mutation in a child with mild myopathy and very mild congenital lipodystrophy. [PMID:24024685]
• Frontiers in Endocrinology • 2023 • A new mutation in the CAVIN1/PTRF gene in two siblings with congenital generalized lipodystrophy type 4: case reports and review of the literature. [PMID:37501786]
• European Journal of Medical Genetics • 2016 • Spectrum of clinical manifestations in two young Turkish patients with congenital generalized lipodystrophy type 4. [PMID:27167729]
• The Journal of Clinical Endocrinology and Metabolism • 2016 • Maladaptative Autophagy Impairs Adipose Function in Congenital Generalized Lipodystrophy due to Cavin-1 Deficiency. [PMID:27144934]

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