Background
Melanocortin 4 receptor
gene (
MC4R
) is an important regulator of food intake, body weight, and blood pressure. Mutations in
MC4R
are associated with the most common form of nonsyndromic monogenic obesity.
MC4R
variations have an autosomal co-/dominant model of inheritance. MC4R screening could reveal individuals previously unrecognized with Mendelian form of obesity for further clinical management and genetic counseling. However, there are limited data regarding
MC4R
variants in patients with obesity from Brazil. The aim of this study was to screen the coding region of the
MC4R
gene in a Brazilian cohort of severely obese adults and to investigate the phenotype–genotype correlation within
MC4R
variant carriers.
Methods
This study comprised 157 adult participants, stratified according to the period of obesity onset. The first group included 97 patients with childhood-onset obesity (0–11 years) and the second group comprised 60 subjects with adolescence/youth-onset obesity (12–21 years). The entire coding region of
MC4R
gene was screened by Sanger sequencing.
Results
As a result, five previously described variants (Met1?, Ser36Thr, Val103Ile, Ile98=, and Phe202Leu) were identified. Met1? is a start lost codon variant, which affects the translation of
MC4R
. It was found in a female patient with childhood-onset obesity. We also compared the anthropometric and metabolic parameters between patients with
MC4R
missense variants (Ser36Thr, Val103Ile, and Phe202Leu) and noncarriers. Patients carrying
MC4R
variants had higher median of waist–hip ratio when compared to noncarriers (
P
=0.048). These missense variants were also associated with hypertension (
P
=0.014). Additionally, Val103Ile carriers had lower diastolic blood pressure and lower systolic blood pressure compared to noncarriers (
P
=0.020 and
P
=0.065, respectively). Val103Ile was also associated with hypertension (
P
=0.003).
Conclusion
This study showed the prevalence of
MC4R
variants in a cohort of Brazilian adults with severe obesity. We also identified significant phenotype differences between carriers and noncarriers of missense variants in our sample, suggesting an important role of
MC4R
on body fat distribution and blood pressure.
Objective: We aimed to identify the frequency of monogenic diabetes, which is poorly studied in multiethnic populations, due to GCK or HNF1A mutations in patients with suggestive clinical characteristics from the Brazilian population, as well as investigate if the MODY probability calculator (MPC) could help patients with their selection. Subjects and methods: Inclusion criteria were patients with DM diagnosed before 35 years; body mass index < 30 kg/m 2 ; negative autoantibodies; and family history of DM in two or more generations. We sequenced HNF1A in 27 patients and GCK in seven subjects with asymptomatic mild fasting hyperglycemia. In addition, we calculated MODY probability with MPC. Results: We identified 11 mutations in 34 patients (32.3%). We found three novel mutations. In the GCK group, six cases had mutations (85.7%), and their MODY probability on MPC was higher than 50%. In the HNF1A group, five of 27 individuals had mutations (18.5%). The MPC was higher than 75% in 11 subjects (including all five cases with HNF1A mutations). Conclusion: Approximately one third of the studied patients have GCK or HNF1A mutations. Inclusion criteria included efficiency in detecting patients with GCK mutations but not for HNF1A mutations (< 20%). MPC was helpful in narrowing the number of candidates for HNF1A screening.
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