Konstanze Miehle1, Joseph Porrmann2, Diana Mitter3, Michael Stumvoll1, Christiane Glaser2, Mathias Fasshauer1,4, Katrin Hoffmann2. 1. Department of Internal Medicine (Endocrinology and Nephrology), University of Leipzig, Leipzig, Germany. 2. Department of Human Genetics, University of Halle, Halle, Germany. 3. Department of Human Genetics, University of Leipzig, Leipzig, Germany. 4. Leipzig University Medical Center, IFB AdiposityDiseases, Leipzig, Germany.
Abstract
OBJECTIVE: Familial partial lipodystrophy type 3 (FPLD3) is an autosomal dominant disorder with loss of subcutaneous adipose tissue at the extremities and metabolic complications such as insulin resistance, hypertriglyceridaemia and hypertension. The aim of this study was to characterize the molecular basis of a family of 5 affected members with FPLD3. METHODS: A 61-year-old female index patient and her relatives were assessed by detailed clinical and biochemical examinations. Sequence analysis of the LMNA and PPARG gene was performed. Structure analysis of the identified mutation was carried out using published X-ray crystal structures. RESULTS: A novel heterozygous PPARG mutation c.1040A>C was identified in all 5 patients of the family but not in unaffected controls. The resulting amino acid substitution p.Lys347Thr is located at the ligand-binding domain (LBD) of the protein and is predicted to disrupt critical molecular interactions to the helix 12 of the LBD. CONCLUSIONS: A novel PPARG mutation leading to FPLD3 is described. The results emphasize the importance of the clinical diagnosis and of further molecular genetic analyses in patients with clinical signs of FPLD but unremarkable LMNA findings.
OBJECTIVE: Familial partial lipodystrophy type 3 (FPLD3) is an autosomal dominant disorder with loss of subcutaneous adipose tissue at the extremities and metabolic complications such as insulin resistance, hypertriglyceridaemia and hypertension. The aim of this study was to characterize the molecular basis of a family of 5 affected members with FPLD3. METHODS: A 61-year-old female index patient and her relatives were assessed by detailed clinical and biochemical examinations. Sequence analysis of the LMNA and PPARG gene was performed. Structure analysis of the identified mutation was carried out using published X-ray crystal structures. RESULTS: A novel heterozygous PPARG mutation c.1040A>C was identified in all 5 patients of the family but not in unaffected controls. The resulting amino acid substitution p.Lys347Thr is located at the ligand-binding domain (LBD) of the protein and is predicted to disrupt critical molecular interactions to the helix 12 of the LBD. CONCLUSIONS: A novel PPARG mutation leading to FPLD3 is described. The results emphasize the importance of the clinical diagnosis and of further molecular genetic analyses in patients with clinical signs of FPLD but unremarkable LMNA findings.
Authors: Julia von Schnurbein; Claire Adams; Baris Akinci; Giovanni Ceccarini; Maria Rosaria D'Apice; Alessandra Gambineri; Raoul C M Hennekam; Isabelle Jeru; Giovanna Lattanzi; Konstanze Miehle; Gabriele Nagel; Giuseppe Novelli; Ferruccio Santini; Ermelinda Santos Silva; David B Savage; Paolo Sbraccia; Jannik Schaaf; Ekaterina Sorkina; George Tanteles; Marie-Christine Vantyghem; Camille Vatier; Corinne Vigouroux; Elena Vorona; David Araújo-Vilar; Martin Wabitsch Journal: Orphanet J Rare Dis Date: 2020-01-15 Impact factor: 4.123