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. 2019 May 7;10(5):342.
doi: 10.3390/genes10050342.

Congenital Leptin Deficiency and Leptin Gene Missense Mutation Found in Two Colombian Sisters with Severe Obesity

Hernan Yupanqui-Lozno  1 , Raul A Bastarrachea  2 , Maria E Yupanqui-Velazco  3 , Monica Alvarez-Jaramillo  4 , Esteban Medina-Méndez  5 , Aida P Giraldo-Peña  6 , Alexandra Arias-Serrano  7 , Carolina Torres-Forero  8 , Angelica M Garcia-Ordoñez  9 , Claudio A Mastronardi  10 , Carlos M Restrepo  11 , Ernesto Rodriguez-Ayala  12 , Edna J Nava-Gonzalez  13 , Mauricio Arcos-Burgos  14 , Jack W Kent Jr  15 , Shelley A Cole  16 , Julio Licinio  17 , Luis G Celis-Regalado  18
Affiliations

Congenital Leptin Deficiency and Leptin Gene Missense Mutation Found in Two Colombian Sisters with Severe Obesity

Hernan Yupanqui-Lozno et al. Genes (Basel). .

Abstract

Background: Congenital leptin deficiency is a recessive genetic disorder associated with severe early-onset obesity. It is caused by mutations in the leptin (LEP) gene, which encodes the protein product leptin. These mutations may cause nonsense-mediated mRNA decay, defective secretion or the phenomenon of biologically inactive leptin, but typically lead to an absence of circulating leptin, resulting in a rare type of monogenic extreme obesity with intense hyperphagia, and serious metabolic abnormalities.

Methods: We present two severely obese sisters from Colombia, members of the same lineal consanguinity. Their serum leptin was measured by MicroELISA. DNA sequencing was performed on MiSeq equipment (Illumina) of a next-generation sequencing (NGS) panel involving genes related to severe obesity, including LEP.

Results: Direct sequencing of the coding region of LEP gene in the sisters revealed a novel homozygous missense mutation in exon 3 [NM_002303.3], C350G>T [p.C117F]. Detailed information and clinical measurements of these sisters were also collected. Their serum leptin levels were undetectable despite their markedly elevated fat mass.

Conclusions: The mutation of LEP, absence of detectable leptin, and the severe obesity found in these sisters provide the first evidence of monogenic leptin deficiency reported in the continents of North and South America.

Keywords: Colombian sisters; LEP gene; congenital leptin deficiency; consanguinity; extreme obesity; novel mutation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Clinical photographs of two Colombian sisters with congenital leptin deficiency with a newly reported mutation in the leptin gene. OBX1 (A) is a 24-year-old female and OBX2 (B) is her 21-year-old sister.
Figure 2
Figure 2
(A) DNA sequencing chromatogram indicating leptin (LEP) gene homozygous mutation c.350G>T (p.Cys117Phe) in severely obese sisters OBX1 and OBX2. (B) DNA sequencing chromatogram indicating LEP gene homozygous mutation c.350G>T (p.Cys117Phe) in the father and mother of the severely obese sisters OBX1 and OBX2, but not in their siblings. (C) Pedigree of the family. The black arrow indicates sister OBX1 (arrow at IV.2) and sister OBX2 (IV.3). This pedigree includes four generations of a highly inbred family, having at least two identified consanguineous unions and four affected people evaluated by the research group, suggesting an autosomal recessive inheritance pattern. We could assume that one variant is carried by the father and sisters. Unfortunately, we do not have genotyping for any of the grandparents still alive. We could only speculate that either one of the grandparents might carry the contributing variant. (D) BMI from the affected sisters, parents, and siblings.
Figure 3
Figure 3
(A) Genomic structure of the LEP gene (wild type), showing all exons, oligonucleotides, and amino acid sequence. (B) Novel mutation in LEP gene–Leptin mRNA (NM_000230.2): c.350G>T (p.C117F) in the severe obese sisters (in-frame transversion of G to T) mutation in nucleotide 350 in the encoding sequence, guanine (G) replaced by thymine (T), causing Cys replacement by Phe in amino acid 117, with lack of intrachain disulfide bond.
See this image and copyright information in PMC

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