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Dunnigan-type familial partial lipodystrophy (FPLD2; [MONDO:0007906]) is an autosomal dominant adipose tissue disorder caused by pathogenic variants in the LMNA gene ([HGNC:6636]), which encodes nuclear lamins A and C. Affected individuals exhibit loss of subcutaneous fat from the limbs and trunk, excess facial and neck adiposity, severe insulin resistance, hypertriglyceridemia, acanthosis nigricans, and early cardiovascular complications. The first non-missense LMNA mutation reported in FPLD2 was a splice-donor variant in intron 8 identified in two sisters with severe metabolic derangements and their mother (2 sisters, 1 mother; [PMID:16636128]).
Over 80 heterozygous LMNA mutations have been linked to FPLD2, predominantly missense substitutions within exon 8 (e.g., at codon 482), as well as splice-site (c.1488+5G>C), deep-intronic, and truncating variants. The variant spectrum includes missense (e.g., p.Arg482Trp), splice (e.g., c.1488+5G>C), and other classes such as p.Arg349Trp and p.Gly465Asp, reflecting diverse effects on lamin A/C structure and function.
Autosomal dominant inheritance is demonstrated by multi-family segregation of LMNA variants. The R482Q substitution co-segregates with FPLD2 in a kindred comprising 23 affected adults ([PMID:10999791]). The homozygous p.R582C mutation yields three individuals with severe generalized lipodystrophy and one heterozygote with partial lipodystrophy ([PMID:30177912]). The splice-donor variant c.1488+5G>C segregates in a single South Asian pedigree (two sisters and their mother) ([PMID:16636128]).
Functional assays confirm that FPLD2-associated LMNA mutations disrupt normal lamin A/C biology. Missense mutants impair lamin A/C–emerin interactions and nuclear envelope assembly, alter chromatin organization, and interfere with adipogenic transcription via SREBP1 binding ([PMID:11929849]). Endothelial cell studies of p.Arg482Trp reveal farnesylated prelamin A accumulation, oxidative stress, and senescence leading to endothelial dysfunction and early atherosclerosis, which can be rescued by statins ([PMID:23846499]). Patient-derived iPSC models carrying p.Arg349Trp replicate nuclear abnormalities and metabolic defects, providing platforms for mechanistic and therapeutic studies ([PMID:31794942]).
Phenotypic heterogeneity is evident: classic heterozygous variants cause partial lipodystrophy with metabolic complications (n=24; [PMID:15773753]), whereas homozygous p.R582H presents with nearly complete fat loss resembling congenital generalized lipodystrophy type 1 ([PMID:32685188]). Variable expressivity within families underscores the influence of genetic modifiers and environment.
Integration of genetic and experimental data yields a definitive gene–disease association. LMNA pathogenic variants act via dominant-negative and haploinsufficiency mechanisms to disrupt nuclear architecture and adipocyte function. Clinical genetic testing, including screening for the recurrent hotspot c.1444C>T (p.Arg482Trp), informs diagnosis and familial risk. Functional insights support targeted therapies—statins for vascular protection and liraglutide for glycemic and lipid control in pediatric patients ([PMID:40619352]). Key take-home: LMNA testing is essential for accurate diagnosis, counseling, and personalized management of Dunnigan-type familial partial lipodystrophy.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrongMultiple pathogenic LMNA variants identified in >100 individuals with FPLD2; reached genetic evidence cap Functional EvidenceModerateCellular and iPSC models, endothelial assays, and adipogenic transcription studies demonstrate mechanistic concordance |