Seven Novel Deleterious LEPR Mutations Found in Early-Onset Obesity: a ΔExon6–8 Shared by Subjects From Reunion Island, France, Suggests a Founder Effect

Huvenne, Hélène; Beyec, Johanne Le; Pépin, Dominique; Alili, Rohia; Kherchiche, Patricia Pigeon; Jeannic, Erwan; Frelut, Marie-Laure; Lacorte, Jean‐Marc; Nicolino, Marc; Viard, A.; Laville, Martine; Ledoux, Séverine; Tounian, P.; Poitou, Christine; Dubern, B.; Clément, Karine

doi:10.1210/jc.2015-1036

Cited by 71 publications

(89 citation statements)

References 32 publications

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“…Patient 2 had hypogonadotropic hypogonadism, which has previously been reported in several LEPR-deficient subjects [2,3,6,8]. In leptin-deficient patients with hypogonadotropic hypogonadism, a normal response to GnRH has been described by some, which was seen as evidence for the hypothalamic origin of hypogonadism [35], but others found a low response to GnRH as we did [2].…”

Section: Discussionsupporting

confidence: 82%

“…The fact that obesity did not develop until adulthood may be interpreted as evidence against a causal role of the obviously congenital LEPR mutation. However, the development of obesity during adulthood was also observed by others in heterozygous subjects [8]. The heterozygous mother and sister have normal weight.…”

Section: Discussionmentioning

confidence: 58%

“…To date, the phenotype has only been described in 25 children [2,3,4,5,6,7,8,9,10]. All were severely obese; in some subjects, additional features were reported, e.g.…”

Section: Introductionmentioning

confidence: 99%

“…All were severely obese; in some subjects, additional features were reported, e.g. (clinical features of) altered immune function/T-cell numbers [3,4,7,10], hypogonadotropic hypogonadism [3,6,8], reduced growth hormone (GH) secretion [2,8], hypothalamic hypothyroidism [2,8], and reduced adult height [3]. No data are available on bone health in these patients, although LEPR is known to be involved in bone metabolism [11,12].…”

Section: Introductionmentioning

confidence: 99%

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Novel Leptin Receptor Mutations Identified in Two Girls with Severe Obesity Are Associated with Increased Bone Mineral Density

Hannema¹,

Wit²,

Houdijk³

et al. 2016

Horm Res Paediatr

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Background: Recessive mutations in the leptin receptor (LEPR) are a rare cause of hyperphagia and severe early-onset obesity. To date, the phenotype has only been described in 25 obese children, some of whom also had altered immune function, hypogonadotropic hypogonadism, reduced growth hormone secretion, hypothalamic hypothyroidism or reduced adult height. We provide a detailed description of the phenotype of 2 affected girls to add to this knowledge. Methods: Whole-exome sequencing and targeted sequencing were used to detect the LEPR mutations. RNA analysis was performed to assess the effect of splice-site mutations. Results: In 2 unrelated girls with severe obesity, three novel LEPR mutations were detected. Longitudinal growth data show normal childhood growth, and in the older girl, a normal adult height despite hypogonadotropic hypogonadism and the lack of an obvious pubertal growth spurt. Bone age is remarkably advanced in the younger (prepubertal) girl, and bone mineral density (BMD) is high in both girls, which might be directly or indirectly related to leptin resistance. Conclusion: The spectrum of clinical features of LEPR deficiency may be expanded with increased BMD. Future observations in LEPR-deficient subjects should help further unravel the role of leptin in human bone biology.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 58%

“…To date, the phenotype has only been described in 25 children [2,3,4,5,6,7,8,9,10]. All were severely obese; in some subjects, additional features were reported, e.g.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel Leptin Receptor Mutations Identified in Two Girls with Severe Obesity Are Associated with Increased Bone Mineral Density

Hannema¹,

Wit²,

Houdijk³

et al. 2016

Horm Res Paediatr

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“…Biallelische Mutationen im Leptinrezeptorgen treten etwas häufiger auf als Mutationen im Leptingen -die Häufigkeit wird in Populationen mit extremer frühkindlicher Adipositas mit 2-3 % angegeben [38]. Auch hier zeigt sich eine Häufung in Gesellschaften mit einem hohen Anteil an konsanguinen Ehen wie z.…”

Section: Epidemiologieunclassified

Monogene Adipositas

Schnurbein

Wabitsch

2017

Medizinische Genetik

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Zusammenfassung Autosomal-rezessiv vererbte Mutationen in den Genen für Leptin, Leptinrezeptor, Proopiomelanocortin (POMC) und Prohormon-Convertase (PC1) führen zu einer ausgeprägten frühkindlichen Adipositas. Patienten mit biologisch inaktivem Leptin oder Leptinmangel können mit humanem rekombinanten Leptin erfolgreich behandelt werden. Für die anderen Patienten hat sich die Behandlung mit einem α‑MSH-Analogon als erfolgreich erwiesen (POMC-Patienten) bzw. befindet sich derzeit in Erprobung. Kodominant vererbte Mutationen im MC4R-Gen stellen die häufigste Form der monogenen Adipositas dar. Eine kausale Therapie ist hier allerdings nicht möglich. Es sind inzwischen noch weitere, autosomal-rezessiv vererbte Genmutationen identifiziert worden, die ebenfalls mit einer ausgeprägten Adipositas assoziiert sind. Die meisten dieser Mutationen liegen in Genen, die in die Signaltransduktion von MC4R oder dem Leptinrezeptor involviert sind. Auch für diese Patienten gibt es aktuell noch keine kausale Therapie. Schlussfolgerung: Bei Patienten mit extremer frühkindlicher Adipositas sollte eine molekulargenetische Diagnostik eingeleitet werden, da die Diagnosestellung für die Betroffenen und ihre Familie eine enorme Erleichterung bedeuten kann. Außerdem gewinnen die Familien Klarheit über das Wiederholungsrisiko und eventuell ist sogar eine kausale oder zumindest optimierte Therapie möglich.

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Genetics of Obesity in Consanguineous Populations: Toward Precision Medicine and the Discovery of Novel Obesity Genes

Saeed

Arslan

Froguel

2018

Obesity

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Objective: Consanguinity has been instrumental in the elucidation of many Mendelian genetic diseases. Here, the unique advantage of consanguineous populations was considered in the quest for genes causing obesity. Methods: PubMed was searched for articles relevant to consanguinity and obesity published between 1995 and 2016. Some earlier articles of interest were also consulted. Results: Although obesity is the most heritable disorder, even in outbred populations, only 2% to 5% of severe obesity cases have so far been proven to be caused by single gene mutations. In some highly consanguineous populations, a remarkably higher proportion of obesity cases because of known and novel monogenic variants has been identified (up to 30%). Conclusions: Combining the power conferred by consanguinity with current large-capacity sequencing techniques should bring new genetic factors and molecular mechanisms to the fore, unveiling a large part of the yet-elusive neurohumoral circuitry involved in the regulation of energy homeostasis and appetite. Importantly, the undertaking of such initiatives is destined to unfold novel targets for the development of precision medicine relevant to different forms of obesity.

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Seven Novel Deleterious LEPR Mutations Found in Early-Onset Obesity: a ΔExon6–8 Shared by Subjects From Reunion Island, France, Suggests a Founder Effect

Cited by 71 publications

References 32 publications

Novel Leptin Receptor Mutations Identified in Two Girls with Severe Obesity Are Associated with Increased Bone Mineral Density

Novel Leptin Receptor Mutations Identified in Two Girls with Severe Obesity Are Associated with Increased Bone Mineral Density

Monogene Adipositas

Genetics of Obesity in Consanguineous Populations: Toward Precision Medicine and the Discovery of Novel Obesity Genes

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