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Prevalence of pathogenetic MC4R mutations in Italian children with early onset obesity, tall stature and familial history of obesity.

Santoro N, Cirillo G, Xiang Z, Tanas R, Greggio N, Morino G, Iughetti L, Vottero A, Salvatoni A, Di Pietro M, Balsamo A, Crinò A, Grandone A, Haskell-Luevano C, Perrone L, del Giudice EM - BMC Med. Genet. (2009)

Bottom Line: The S127L (C380T), found in three unrelated children, had been described and functionally characterized previously.The Q307X (C919T) and the Y332H (T994C) mutations were found in two patients.Functional studies showed that only Q307X impaired protein function.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dipartimento di Pediatria F, Fede, Seconda Università degli Studi di Napoli, Napoli, Italy. nicolasantoro@hotmail.com

ABSTRACT

Background: Melanocortin-4-receptor (MC4R) mutations represent the most frequent genetic cause of non-syndromic early onset obesity. Children carrying MC4R mutations seem to show a particular phenotype characterized by early onset, severe obesity and high stature. To verify whether MC4R mutations are associated with this particular phenotype in the Italian pediatric population, we decided to screen the MC4R gene in a group of obese children selected on the basis of their phenotype.

Methods: To perform this study, a multicentric approach was designed. Particularly, to be enrolled in the study subjects needed to meet the following criteria: Body mass index > or = 3 deviation scores according to age and sex, familiar history of obesity (at least one parent obese), obesity onset before the 10 years old, height > or = 2 deviation scores. The coding region of MC4R gene was screened in 240 obese children (mean age 8.3 +/- 3.1, mean BMI 30.8 +/- 5.4) and in 200 controls (mean age 8.1 +/- 2.8; mean BMI 14.2 +/- 2.5).

Results: Three mutations have been found in five obese children. The S127L (C380T), found in three unrelated children, had been described and functionally characterized previously. The Q307X (C919T) and the Y332H (T994C) mutations were found in two patients. Functional studies showed that only Q307X impaired protein function.

Conclusion: The low prevalence of MC4R mutations (1.6%) in this group of obese children selected according to the obesity degree, the tall stature and the family history of obesity was similar to the prevalence observed in previous screenings performed in obese adults and in not phenotypically selected obese children.

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Functional Agonist Data. Illustration of the activity of α-MSH, ACTH1–24, β-MSH, γ2-MSH, and synthetic agonist JRH887–9 at the wild type MC4R, Q307X MC4R and Y332H MC4R. Agonists did not evocate any response by binding the Q307X MC4R. When the agonists were binding the Y332H MC4R the evocated response was similar to that observed for the wild type.
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Figure 3: Functional Agonist Data. Illustration of the activity of α-MSH, ACTH1–24, β-MSH, γ2-MSH, and synthetic agonist JRH887–9 at the wild type MC4R, Q307X MC4R and Y332H MC4R. Agonists did not evocate any response by binding the Q307X MC4R. When the agonists were binding the Y332H MC4R the evocated response was similar to that observed for the wild type.

Mentions: When the ability of the Q307X and Y332H mutated MC4Rs to generate cAMP in response to increasing concentrations of α-MSH was tested, the Q307X MC4R did not evocate any response, while the response evocated by the agonist binding the Y332H MC4R (6.29 ± 1.93) was similar to that evocated by binding the wild type receptor (6.85 ± 3.23) (figure 3)


Prevalence of pathogenetic MC4R mutations in Italian children with early onset obesity, tall stature and familial history of obesity.

Santoro N, Cirillo G, Xiang Z, Tanas R, Greggio N, Morino G, Iughetti L, Vottero A, Salvatoni A, Di Pietro M, Balsamo A, Crinò A, Grandone A, Haskell-Luevano C, Perrone L, del Giudice EM - BMC Med. Genet. (2009)

Functional Agonist Data. Illustration of the activity of α-MSH, ACTH1–24, β-MSH, γ2-MSH, and synthetic agonist JRH887–9 at the wild type MC4R, Q307X MC4R and Y332H MC4R. Agonists did not evocate any response by binding the Q307X MC4R. When the agonists were binding the Y332H MC4R the evocated response was similar to that observed for the wild type.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2664798&req=5

Figure 3: Functional Agonist Data. Illustration of the activity of α-MSH, ACTH1–24, β-MSH, γ2-MSH, and synthetic agonist JRH887–9 at the wild type MC4R, Q307X MC4R and Y332H MC4R. Agonists did not evocate any response by binding the Q307X MC4R. When the agonists were binding the Y332H MC4R the evocated response was similar to that observed for the wild type.
Mentions: When the ability of the Q307X and Y332H mutated MC4Rs to generate cAMP in response to increasing concentrations of α-MSH was tested, the Q307X MC4R did not evocate any response, while the response evocated by the agonist binding the Y332H MC4R (6.29 ± 1.93) was similar to that evocated by binding the wild type receptor (6.85 ± 3.23) (figure 3)

Bottom Line: The S127L (C380T), found in three unrelated children, had been described and functionally characterized previously.The Q307X (C919T) and the Y332H (T994C) mutations were found in two patients.Functional studies showed that only Q307X impaired protein function.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dipartimento di Pediatria F, Fede, Seconda Università degli Studi di Napoli, Napoli, Italy. nicolasantoro@hotmail.com

ABSTRACT

Background: Melanocortin-4-receptor (MC4R) mutations represent the most frequent genetic cause of non-syndromic early onset obesity. Children carrying MC4R mutations seem to show a particular phenotype characterized by early onset, severe obesity and high stature. To verify whether MC4R mutations are associated with this particular phenotype in the Italian pediatric population, we decided to screen the MC4R gene in a group of obese children selected on the basis of their phenotype.

Methods: To perform this study, a multicentric approach was designed. Particularly, to be enrolled in the study subjects needed to meet the following criteria: Body mass index > or = 3 deviation scores according to age and sex, familiar history of obesity (at least one parent obese), obesity onset before the 10 years old, height > or = 2 deviation scores. The coding region of MC4R gene was screened in 240 obese children (mean age 8.3 +/- 3.1, mean BMI 30.8 +/- 5.4) and in 200 controls (mean age 8.1 +/- 2.8; mean BMI 14.2 +/- 2.5).

Results: Three mutations have been found in five obese children. The S127L (C380T), found in three unrelated children, had been described and functionally characterized previously. The Q307X (C919T) and the Y332H (T994C) mutations were found in two patients. Functional studies showed that only Q307X impaired protein function.

Conclusion: The low prevalence of MC4R mutations (1.6%) in this group of obese children selected according to the obesity degree, the tall stature and the family history of obesity was similar to the prevalence observed in previous screenings performed in obese adults and in not phenotypically selected obese children.

Show MeSH
Related in: MedlinePlus