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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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Family trees of the probands carrying the S127L variant. This variant was found in three unrelated subjects from three different obesity Services. A show the family tree of subject 1 (see Table 1). The figure shows that all the carriers but the subject I 2 (grandmother) were obese. B and C show the family trees of patients 2 and 3, respectively (see Table 1). The half black square indicates males heterozygotes for the mutation, the half black circle indicates the females heterozygotes for the mutation.
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Figure 1: Family trees of the probands carrying the S127L variant. This variant was found in three unrelated subjects from three different obesity Services. A show the family tree of subject 1 (see Table 1). The figure shows that all the carriers but the subject I 2 (grandmother) were obese. B and C show the family trees of patients 2 and 3, respectively (see Table 1). The half black square indicates males heterozygotes for the mutation, the half black circle indicates the females heterozygotes for the mutation.

Mentions: Molecular screening of the MC4R showed the substitution of a serine with a leucine at the codon 127 (S127L) consequent to the substitution of a cytosine in position 380 with a thymidine, a substitution of the glutamine with a stop codon at the codon 307 (Q307X) caused by the substitution of a cytosine with a thymidine in position 919 (C919T) and the substitution of a tyrosine with a histidine at the codon 332 (Y332H) caused by the substitution of a thymidine with a cytosine in position 994 (T994C). The S127L mutation was found in three non-consanguineous individuals from three different centers (Modena, Bologna, Napoli), the two mutations, Y332H and Q307X were found in a child from Napoli and in a child from Ferrara, respectively (table 1). Four out of five families were investigated and mutations co-segregated with obesity in 9 out of 10 individuals harboring a variant (figures 1 and 2).


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)

Family trees of the probands carrying the S127L variant. This variant was found in three unrelated subjects from three different obesity Services. A show the family tree of subject 1 (see Table 1). The figure shows that all the carriers but the subject I 2 (grandmother) were obese. B and C show the family trees of patients 2 and 3, respectively (see Table 1). The half black square indicates males heterozygotes for the mutation, the half black circle indicates the females heterozygotes for the mutation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Family trees of the probands carrying the S127L variant. This variant was found in three unrelated subjects from three different obesity Services. A show the family tree of subject 1 (see Table 1). The figure shows that all the carriers but the subject I 2 (grandmother) were obese. B and C show the family trees of patients 2 and 3, respectively (see Table 1). The half black square indicates males heterozygotes for the mutation, the half black circle indicates the females heterozygotes for the mutation.
Mentions: Molecular screening of the MC4R showed the substitution of a serine with a leucine at the codon 127 (S127L) consequent to the substitution of a cytosine in position 380 with a thymidine, a substitution of the glutamine with a stop codon at the codon 307 (Q307X) caused by the substitution of a cytosine with a thymidine in position 919 (C919T) and the substitution of a tyrosine with a histidine at the codon 332 (Y332H) caused by the substitution of a thymidine with a cytosine in position 994 (T994C). The S127L mutation was found in three non-consanguineous individuals from three different centers (Modena, Bologna, Napoli), the two mutations, Y332H and Q307X were found in a child from Napoli and in a child from Ferrara, respectively (table 1). Four out of five families were investigated and mutations co-segregated with obesity in 9 out of 10 individuals harboring a variant (figures 1 and 2).

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