Seven novel deleterious LEPR mutations found in early-onset obesity: a ΔExon6-8 shared by subjects from Reunion Island, France, suggests a founder effect.
BACKGROUND
Infrequent mutations have been reported in the leptin receptor (LEPR) gene in humans with morbid obesity and endocrine disorders. However LEPR mutations are rarely examined in large populations from different ethnicities in a given country.


OBJECTIVE
We estimated the prevalence of LEPR mutations in French patients with severe obesity and evaluated mutated patients' phenotype.


METHODS
We sequenced the LEPR gene in 535 morbidly obese French participants. We conducted clinical investigations to determine whether individuals with a novel shared mutation display particular characteristics relative to obesity history, body composition, hormonal functions, and the outcome of bariatric surgery.


RESULTS
We identified 12 patients with a novel LEPR mutation (p.C604G, p.L786P, p.H800_N831del, p.Y422H, p.T711NfsX18, p.535-1G>A, p.P166CfsX7). Six unrelated subjects were carriers of the p.P166CfsX7 mutation leading to deletion overlapping exons 6 to 8. All subjects originated from Reunion Island (France). Their clinical features (severe early-onset obesity, food impulsivity, and hypogonadotropic hypogonadism) did not differ from other new LEPR mutation carriers. Results concerning weight loss surgery were inconsistent in homozygous LEPR mutation carriers. Heterozygous LEPR mutation carriers exhibited variable severity of obesity and no endocrine abnormality.


CONCLUSIONS
Among seven newly discovered LEPR mutations in this French obese population, we identified a LEPR frameshift mutation shared by six subjects from Reunion Island. This observation suggests a founder effect in this Indian Ocean island with high prevalence of obesity and supports a recommendation for systematic screening for this mutation in morbidly obese subjects in this population.
Institute of Cardiometabolism and Nutrition (H.H., R.A., J.-M.L., P.T., C.P., B.D., K.C.), Pitié-Salpêtrière Hospital, Nutrition Department, Paris F-75013, France; Sorbonne Universities (H.H., J.L.B., J.-M.L., C.P., K.C.), University Pierre et Marie Curie-Paris 6, Paris F-75006, France; INSERM (H.H., R.A., P.T., C.P., B.D., K.C.), Unité Mixte de Recherche (UMR)_S U1166, Nutriomics, Paris F-75013, France; Groupement des Hôpitaux de l'Institut Catholique de Lille (H.H.), St-Vincent de Paul Hospital, Department of Pediatrics, Lille F-59000, France; Assistance Publique-Hôpitaux de Paris (J.L.B., D.P., J.-M.L.), Pitié-Salpêtrière Hospital, Department of Biochemical Endocrinology and Oncology, Nutrigénétique, Paris F-75013, France; INSERM (J.L.B.), UMR_S U1149, Université François-Rabelais de Médecine Paris Diderot, Paris F-75018, France; Félix-Guyon-Bellepierre Hospital (P.P.K.), Department of Pediatrics, St-Denis F-97405, Reunion, France; St François d'Assise Association (E.J.), Department of Pediatric Nutrition, St-Denis F-97405, Reunion, France; Assistance Publique Hôpitaux de Paris (M.-L.F.), Bicêtre Hospital, Department of Pediatric Endocrinology and Diabetology, Kremlin-Bicêtre F-94270, France; INSERM (J.-M.L.), Integrative Biology of Atherosclerosis, UMR_S U1166, Paris F-75013, France; Mother and Child Hospital (M.N.), Department of Pediatric Endocrinology, Lyon F-69000, France; Robert Debré Hospital (A.V.), Department of Endocrinology, Reims F-51100, France; Lyon-Sud Hospital (M.L.), Department of Endocrinology, Diabetology, and Nutrition, Lyon F-69000, France; Assistance Publique-Hôpitaux de Paris (S.L.), Functional Explorations, Louis Mourier Hospital, Obesity Center, Colombes F-92700, France; and Assistance Publique-Hôpitaux de Paris (P.T., B.D.), Department of Pediatric Nutrition and Gastroenterology, Armand-Trousseau Hospital, Paris F-75571, France.
Hélène
H
Huvenne
Johanne
J
Le Beyec
Dominique
D
Pépin
Rohia
R
Alili
Patricia Pigeon
PP
Kherchiche
Erwan
E
Jeannic
Marie-Laure
ML
Frelut
Jean-Marc
JM
Lacorte
Marc
M
Nicolino
Amélie
A
Viard
Martine
M
Laville
Séverine
S
Ledoux
Patrick
P
Tounian
Christine
C
Poitou
Béatrice
B
Dubern
Karine
K
Clément
D000328:Adult; D001823:Body Composition / Q000235:genetics; D005091:Exons; D005260:Female; D018703:Founder Effect; D005602:France; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D054411:Receptors, Leptin / Q000235:genetics*
D054411:Receptors, Leptin