Familial partial lipodystrophy linked to a novel peroxisome proliferator activator receptor -γ (PPARG) mutation, H449L: a comparison of people with this mutation and those with classic codon 482 Lamin A/C (LMNA) mutations.

To describe the phenotype associated with a novel heterozygous missense PPARG mutation discovered in a Turkish family and to compare the fat distribution and metabolic characteristics of subjects with the peroxisome proliferator activator receptor -γ (PPARG) mutation with those of a cluster of patients with familial partial lipodystrophy with classic codon 482 Lamin A/C (LMNA) mutations. The study involved four subjects with familial partial lipodystrophy who had a novel PPARG mutation (H449L) and six subjects with classic codon 482 LMNA mutations (R482W). Compared with subjects with LMNA R482W mutation, fat loss was generally less prominent in subjects with the PPARG H449L mutation. Partial fat loss was limited to the extremities, whilst truncal fat mass was preserved. The PPARG H449L mutation was associated with insulin resistance, hypertriglyceridaemia and non-alcoholic fatty liver disease in all affected subjects, but the severity was variable. Three out of four mutation carriers had overt diabetes or impaired glucose tolerance. Pioglitazone therapy in these three individuals resulted in a modest improvement in their metabolic control, and regular menstrual cycles in the two female subjects. We suggest that relatively modest fat loss in patients with PPARG mutations may render the recognition of the syndrome more difficult in routine clinical practice. The PPARG H449L mutation is associated with insulin resistance and metabolic complications, but their severity is variable among the affected subjects.

Demir T ，Onay H ，Savage DB ，Temeloglu E ，Uzum AK ，Kadioglu P ，Altay C ，Ozen S ，Demir L ，Cavdar U ，Akinci B ... -  《-》

Clinical presentations, metabolic abnormalities and end-organ complications in patients with familial partial lipodystrophy.

Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by partial lack of subcutaneous fat. This multicenter prospective observational study included data from 56 subjects with FPLD (18 independent Turkish families). Thirty healthy controls were enrolled for comparison. Pathogenic variants of the LMNA gene were determined in nine families. Of those, typical exon 8 codon 482 pathogenic variants were identified in four families. Analysis of the LMNA gene also revealed exon 1 codon 47, exon 5 codon 306, exon 6 codon 349, exon 9 codon 528, and exon 11 codon 582 pathogenic variants. Analysis of the PPARG gene revealed exon 3 p.Y151C pathogenic variant in two families and exon 7 p.H477L pathogenic variant in one family. A non-pathogenic exon 5 p.R215Q variant of the LMNB2 gene was detected in another family. Five other families harbored no mutation in any of the genes sequenced. MRI studies showed slightly different fat distribution patterns among subjects with different point mutations, though it was strikingly different in subjects with LMNA p.R349W pathogenic variant. Subjects with pathogenic variants of the PPARG gene were associated with less prominent fat loss and relatively higher levels of leptin compared to those with pathogenic variants in the LMNA gene. Various metabolic abnormalities associated with insulin resistance were detected in all subjects. End-organ complications were observed. We have identified various pathogenic variants scattered throughout the LMNA and PPARG genes in Turkish patients with FPLD. Phenotypic heterogeneity is remarkable in patients with LMNA pathogenic variants related to the site of missense mutations. FPLD, caused by pathogenic variants either in LMNA or PPARG is associated with metabolic abnormalities associated with insulin resistance that lead to increased morbidity.

Akinci B ，Onay H ，Demir T ，Savas-Erdeve Ş ，Gen R ，Simsir IY ，Keskin FE ，Erturk MS ，Uzum AK ，Yaylali GF ，Ozdemir NK ，Atik T ，Ozen S ，Yurekli BS ，Apaydin T ，Altay C ，Akinci G ，Demir L ，Comlekci A ，Secil M ，Oral EA ... -  《-》

The novel loss of function Ile354Val mutation in PPARG causes familial partial lipodystrophy.

Padova G ，Prudente S ，Vinciguerra F ，Sudano D ，Baratta R ，Bellacchio E ，Trischitta V ，Vallone A ，Sciacca L ，Frittitta L ... -  《-》

New PPARG mutation leads to lipodystrophy and loss of protein function that is partially restored by a synthetic ligand.

Lüdtke A ，Buettner J ，Schmidt HH ，Worman HJ ... -  《-》

Peroxisome proliferator-activated receptor-gamma C190S mutation causes partial lipodystrophy.

Lüdtke A ，Buettner J ，Wu W ，Muchir A ，Schroeter A ，Zinn-Justin S ，Spuler S ，Schmidt HH ，Worman HJ ... -  《-》