Leptin Receptor Deficiency

A number sign (#) is used with this entry because leptin receptor deficiency (LEPRD) is caused by homozygous mutation in the LEPR gene (601007) on chromosome 1p31.

Description

Leptin receptor deficiency is characterized by severe early-onset obesity, major hyperphagia, hypogonadotropic hypogonadism, and neuroendocrine/metabolic dysfunction (summary by Dehghani et al., 2018).

Clinical Features

Clement et al. (1998) described a consanguineous family of Kabylian (Berber of northern Algeria) origin in which 3 of 9 sibs had morbid obesity with onset in early childhood. The affected sisters had normal birth weights, but developed severe obesity in the first months of life. They showed abnormal eating behaviors resembling those seen in Prader-Willi syndrome (PWS; 176270) and in individuals with anatomic damage of the hypothalamic area; behavior included fighting with other children for food, impulsivity, and stubbornness. Psychologic testing showed emotional lability and social disability, but no mental retardation. Core temperature and glucose metabolism were normal, as were ACTH and cortisol, but growth hormone and thyrotropin levels were low. The girls did not spontaneously develop puberty and had low estradiol, LH, and FSH levels consistent with central hypogonadism. These results suggested that leptin (164160) and the leptin receptor are important physiologic regulators of several endocrine functions in humans. Clement et al. (1998) considered their results to indicate that leptin is an important physiologic regulator of several endocrine functions in humans.

Farooqi et al. (2007) identified 7 homozygotes for mutations in the LEPR gene among 300 patients with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families. Affected individuals were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these patients. Their clinical features were less severe than those of patients with congenital leptin deficiency (614962).

Dehghani et al. (2018) reported a large consanguineous family in which 9 members, aged 3 to 36 years, had severe early-onset obesity. All affected members had normal head circumference and weight at birth. Weight gain occurred rapidly shortly after birth, leading to severe obesity in early infancy. Affected members had marked hyperphagia and aggressive food-seeking behaviors. No abnormalities were observed on clinical examination, and development and height were normal. Affected members also had an increased rate of intestinal and respiratory tract infections and a longer period of recovery from these infections. The 2 affected adult females had extremely high body mass index and hypogonadal infertility, whereas the body mass index of the 2 affected adult males declined around onset of puberty with preservation of fertility. Dehghani et al. (2018) suggested that there might be a gender-specific effect on body weight regulation in patients with this condition.

Molecular Genetics

In 3 morbidly obese sisters from a consanguineous Berber family, Clement et al. (1998) found homozygosity for a mutation in the LEPR gene, a G-to-A transition at the +1 position of intron 16 (601007.0002).

To determine the prevalence of pathogenic LEPR mutations in severely obese patients, Farooqi et al. (2007) sequenced LEPR in 300 patients with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families. Eight (3%) of the 300 patients had nonsense or missense LEPR mutations, including 7 homozygotes and 1 compound heterozygote. All missense mutations resulted in impaired receptor signaling.

In a consanguineous Iranian family in which 9 members had severe early-onset obesity mapped to chromosome 1p31.3, Dehghani et al. (2018) sequenced the LEPR gene and identified homozygosity for a nonsense mutation (Y155X; 601007.0006). The mutation segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, gnomAD, GME Variome Project, or Iranome databases.

Other Features

Lonnqvist et al. (1995) found overexpression of the human OB gene (LEP) in subcutaneous and omental adipose tissue in massively obese persons. Hamilton et al. (1995) likewise reported that OB mRNA expression is elevated in ex vivo omental adipocytes isolated from massively obese humans despite the absence of an identifiable mutation in the OB gene. This led them to speculate that this increased expression results from an insensitivity to the putative regulatory function(s) of the OB gene product. Maffei et al. (1995) found that mice with lesions of the hypothalamus, as well as mice mutant at the db locus (Lepr), expressed a 20-fold higher level of ob RNA in adipose tissue. These data suggested that both the db gene and the hypothalamus are downstream of the ob gene in the pathway that regulates adipose tissue mass and are consistent with previous experiments, suggesting that the db locus encodes the ob receptor.