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ch Hainer,
Jan Lebl,
Torben Hansen and
Oluf Pedersen
Department of Pediatrics and Center for Research of Diabetes, Metabolism, and Nutrition (I.H., M.F.), Third Faculty of Medicine, Charles University, 100 34 Prague 10, Czech Republic; Steno Diabetes Center and Hagedorn Research Institute (L.H.L., T.H., O.P.), Gentofte, DK-2820 Copenhagen, Denmark; Department of Pharmacology (B.H.), University of Copenhagen, DK-2200 Copenhagen, Denmark; Obesity Management Center (V.H.), Institute of Endocrinology, 116 94 Prague, Czech Republic; Department of Pediatrics (J.L.), Second Faculty of Medicine, Charles University, 15006 Prague 5, Czech Republic; Danish Epidemiology Science Center (L.H.L.), Institute of Preventive Medicine, Copenhagen University Hospital, DK-1357 Copenhagen, Denmark; and Faculty of Health (O.P.), University of Aarhus, DK-8000 C Aarhus, Denmark
Address all correspondence and requests for reprints to: Irena Hainerová, M.D., Department of Pediatrics, 
robárova 50, 100 34 Prague 10, Czech Republic. E-mail: ihainer{at}hotmail.com.
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Abstract |
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Aims: The aims of this study were the following: 1) to estimate the prevalence of MC4R mutations in obese Czech children; 2) to evaluate phenotypic features of the mutation carriers; 3) to compare weight, height, and body mass index of MC4R mutation carriers with noncarriers in longitudinal studies; 4) to determine the effect of a weight management program among MC4R mutation carriers; and 5) to perform a functional analysis of a novel variant.
Subjects and Methods: We analyzed the coding region of MC4R in a cohort of 289 Czech children and adolescents with early-onset obesity by direct sequencing. Information on weight, height, body mass index, baseline biochemical data, and a weight loss follow-up study was obtained. In vitro functional analysis of one novel variant was performed.
Results: We identified six different mutations in seven probands: one novel missense mutation Cys84Arg and five previously reported variants, Arg7Cys, Ser19fsdelA, Phe51Leu, Ser127Leu, and Gly181Asp. The Gly181Asp variant was detected in one homozygous carrier from unrelated parents. None of the mutation carriers fulfilled the MC4R syndrome criteria. A comparison of anthropometrics in mutation carriers and noncarriers during 13 yr of follow-up did not reveal any significant differences. MC4R mutation carriers exhibited a similar ability to lose weight as obese noncarriers. The novel variant Cys84Arg showed a significant reduction in cAMP signal properties of the MC4R.
Conclusions: Among obese Czech children, we found a prevalence of 2.4% of MC4R homozygous and heterozygous mutations and showed a similar response to diet management of MC4R mutation carriers and noncarriers.
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Introduction |
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MC4R is a 322-amino acid protein encoded by a single exon localized on chromosome 18q22. This G protein-coupled receptor is expressed in many neurons in several areas of brain including hypothalamus and is involved in appetite regulation (7). Anorexigenic pathways are stimulated by the action of the MC4R agonist 
-MSH and antagonized by the agouti-related peptide (AGRP) (7).
More than 90 different obesity-associated mutations of MC4R, most of which are missense mutations leading to either total or partial loss of function, have so far been reported (8). The phenotype of carriers with functional mutations varies considerably in their effect on body weight (5, 9, 10, 11). One of the first studies of children with pathogenic MC4R mutations led to the definition of the MC4R syndrome, which is characterized by early-onset obesity, increased linear growth, increased body fat and fat-free mass, increased bone mineral density, hyperphagia, and hyperinsulinemia (6). Furthermore, Farooqi et al. (6) observed that hyperinsulinemia of obese subjects with MC4R deficiency seems to decline with age (adulthood) together with the hyperphagia. However, several studies have not replicated this finding (5, 9, 13, 14). In the same study by Farooqi et al., homozygote MC4R carriers showed an increased ad libitum food intake, compared with their wild-type relatives, a finding that has not been reproduced (5). The quantitative effect of functionally relevant MC4R mutations in adult male and female MC4R mutation carriers has in a large family study been shown to confer an increased risk of obesity when compared with family members without mutations in this locus (15). Recently Lubrano-Berthelier et al. (16) found a similar prevalence of MC4R mutations in subjects with childhood obesity, compared with adult-onset obesity.
Two missense variants, Val103Ile and Ile251Leu, in 3 and 1% of the examined populations, respectively, do not, however, predispose to obesity, and these mutations do not lead to any changes in receptor function (17, 18). Interestingly, a family-based study and metaanalyses have shown that the 103Ile variant is associated with a lower body mass index (BMI) (19, 20). Subsequently the effect was confirmed in a population-based study (21). A more recent study described the slightly improved receptor function conferred by the 103Ile allele, which is in accordance to the weight-reducing effect of this allele (22).
The aim of this study was to estimate the prevalence of MC4R mutations in a cohort of Czech children and adolescents with severe early-onset obesity and to assess whether these mutations cosegregate with obesity. In addition, we delineated the phenotypic expression of the MC4R mutations in the probands and their families in relation to the reported phenotypic features and investigated whether anthropometrics throughout childhood differ between mutation and nonmutation carriers. Finally, we ascertained responses to weight reduction management in MC4R mutation as well as nonmutation carriers and performed functional analysis of one novel variant.
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Subjects and Methods |
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We examined a cohort of 289 unrelated obese children and adolescents (157 girls and 132 boys) aged 1–18 yr for mutations of MC4R. The probands were included in the present study if obesity started before the age of 11 yr and if BMI (kilograms per square meter) retrospectively evaluated exceeded the 97th percentile for sex and age according to Czech national references (23). The mean Z-score of BMI was 4.3 ± 1.7, and the mean age at obesity onset was 4.9 ± 3.1 yr (range 0.5–11 yr).
The children were recruited during the years 2003 and 2004 from pediatric endocrinologists and centers specialized in weight management for children and adolescents. Family members of four carriers of MC4R mutations were recontacted and asked to participate in an extended family investigation. Family members of the remaining MC4R probands were not available for further investigation. Fifty-three unrelated normal-weight control subjects (28 females and 25 males) aged 5–44 yr were recruited from the Department of Pediatrics in Prague and were screened for the novel MC4R variant that was identified in the present study.
Parents of all examined children and adolescents and all examined adult subjects signed an informed consent before the initiation of study procedures. The study protocol was approved by the Ethics Committee of the Third Faculty of Medicine, Charles University in Prague, and was in accordance with the Helsinki declaration II.
Phenotypic studies
From all 289 probands, information on birth weight and length, follow-up weight and height, and medical history was obtained from the medical records provided by general pediatricians. Information on breast-feeding, eating habits, and physical activity was obtained by interviewing parents according to questionnaires. Height was measured to the nearest 0.5 cm at the examination. Body weight (in underwear and without shoes) was measured on calibrated balances or an electronic scale to the nearest 100 g. BMI was calculated as body weight in kilograms divided by the square of the height in meters. Z-scores of BMI, height, and weight were calculated at the age of 1, 1.5, 3, 5, 7, 9, 11, and 13 yr with data obtained from the Czech population as a reference (23). The Z-score represents the number of SDs an individual subject deviates from the mean BMI of the age- and sex-matched general population. A positive Z-score represents a value above the mean, and a negative Z-score stands for a value below the mean. In one third of the cohort, waist and hip circumferences were available.
Four adolescents (one girl, three boys; age range 13–17 yr; BMI range 26.0–45.6 kg/m2) carrying mutant MC4R allele(s) and 85 obese nonmutation carriers as control subjects (46 girls, 39 boys; age range 8.5–17 yr; BMI range 23.5–42.4 kg/m2) underwent a weight reduction program for a 6-wk period. One mutation carrier (boy; aged 6 yr, BMI 20.2 kg/m2) and 21 obese mutation noncarriers as control subjects (11 girls, 10 boys; age range 6–13 yr; BMI range 25–34 kg/m2) participated in the weight study for 3 wk. The weight response was ascertained as the difference in BMI Z-scores before and after the weight reduction regimen and compared between mutation carriers and noncarriers who had undergone the same duration of the intervention. The weight management program was provided on an in-patient basis in three centers specialized in weight management for children (Karlovy Vary, Podbrady, and Vrchlabí, Czech Republic) within a period of 3 or 6 wk and was strictly medically supervised. Children and adolescents had intensive physical exercise 3.5–4.0 h/d: the exercise included swimming, ball games, fitness, and hiking 4–10 km/d combined with an energy-restricted diet (5–7 MJ/d served as six daily meals; fat 
30% and total carbohydrates of 50–55% of the daily energy intake). The program was accompanied by educational courses provided by physicians and dietitians and psychotherapeutic intervention. The body weight was estimated daily and individually evaluated by a physician twice weekly. The participants had no access to additional food except for one weekend during the 6 wk (or 3 wk for controls) spent with their parents.
Body circumferences were measured by standard procedures. Body composition and bone mineral density were determined by whole-body dual x-ray absorptiometry (QDR 2000; Hologic, Bedford, MA). Bone mineral density was compared with age- and sex-specific data (24). All participants of the extended investigation were asked to fill in the Eating Inventory, the Night Eating Syndrome questionnaire, and Binge Eating Disorder (BED) questionnaires.
Biochemical variables
In 30% of the cohort of 289 subjects, baseline biochemical data were available from the general pediatricians or obtained before the start of the weight reduction period. Blood samples of available MC4R mutation carriers were also collected approximately 8 months after the end of the weight-reducing intervention. All samples were collected after an overnight fast and analyzed for plasma glucose, serum levels of lipids, alanine aminotransferase, 
-glutamyltranspeptidase, thyroid-stimulating hormone, free T4, free T3, prolactin, FSH, LH, IGF-I, and SHBG using standard assays (Laboratories of the Institute of Endocrinology, Prague, Czech Republic). Serum insulin was assessed by immunoelectrochemoluminiscence (Roche Diagnostics GmbH, Mannheim, Germany).
Mutation analysis of the coding region of MC4R
Genomic DNA was extracted from whole blood using the QIAamp DNA blood kit (QIAGEN GmbH, Hilden, Germany). Detailed description of primers and PCR conditions can be obtained by request to the corresponding author. The coding region was directly re-sequenced using an ABI Prism dye primer cycle sequencing kit with Ampli-taq DNA Polymerase. Resulting re-sequences were aligned and analyzed on ABI Prism 3100 genetic analyzer (Applied Biosystems, Foster City, CA).
Functional analysis
The human MC4R cDNA was cloned by PCR from a brain cDNA library. After addition of a hemagglutinin tag in the amino-terminal part of the receptor, it was cloned into a pcDNA3 vector (Invitrogen, Carlsbad, CA). The Cys84Arg mutant was introduced by PCR using the overlap expression method. The PCR products were digested with the restriction endonucleases BamHI and EcoRI, purified and cloned into the FLAG-tagged vector pCMV-Tag (Stratagene, La Jolla, CA). All PCR experiments were performed using pfu polymerase (Stratagene) according to the instruction of the manufacturer. The mutation and wild-type constructs were verified by restriction endonuclease mapping and subsequent DNA sequence analysis using an ABI 310 automated sequencer (Applied Biosystems).
COS-7 cells were grown DMEM 1885 supplemented with 10% fetal calf serum, 2 mM glutamine, and 0.01 mg/ml gentamicin. The expression plasmids containing the cDNAs encoding the wild-type or the mutated receptors were transiently expressed after transfection according to the calcium phosphate precipitation method (25), and assays were performed 48 h after transfection.
COS-7 cells (2.5 x 105 cells/well) were incubated for 24 h with 2 µCi of [3H]adenine (TRK 311; Amersham Pharmacia Biotech, Piscataway, NJ) in 1 ml medium. Cells were washed twice and incubated for 15 min at 37 C in 1 ml of freshly prepared binding buffer supplemented with 1 mM isobutylmethylxanthine (I5879; Sigma, St. Louis, MO), 40 µg/ml bacitracin, and various concentrations of ligands or 50 µM forskolin. After incubation cells were placed on ice, medium was removed, and cells were lysed with 1 ml of 5% (wt/vol) trichloroacetic acid, supplemented with 0.1 mM cAMP and 0.1 mM ATP for 30 min. The lysis mixtures were loaded onto a Dowex 50W-X4 (142-1351; Bio-Rad, Hercules, CA) column (Bio-Rad, polyprep columns, 731-1550), which was washed with 2 ml of water and placed on top of alumina columns (Sigma; A9003) and washed again with 10 ml of water. The columns were eluted with 6 ml of 0.1 M imidazole (Sigma; I0125) into 15 ml of scintillation fluid (HIGHSAFE III: GE Healthcare, Little Chalfont, Buckinghamshire, UK). Columns were reused up to 10 times. Dowex columns were regenerated by adding 10 ml of 2 N HCl followed by 10 ml of water and the alumina columns by adding 2 ml of 1 M imidazole, 10 ml of 0.1 M imidazole, and finally 5 ml of water. All assays were run in duplicates.
Statistical analysis
Differences between groups were tested using a general linear model. Analyses were made using Statistical Package of Social Science for Windows (version 12.0; SPSS, Inc., Chicago, IL). P < 0.05 was considered significant without correction for multiple testing.
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Results |
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). The other four missense mutations, Arg7Cys, Phe51Leu, Ser127Leu, and Gly181Asp, and one frameshift mutation, Ser19fsdelA, have already been reported and are presented in Table 1 together with their functional relevance. The Gly181Asp missense mutation was found in homozygous form in the first child of two siblings born of unrelated parents. We detected one subject carrying the previously identified polymorphism Ile251Leu. The Val103Ile was found with a carrier frequency of 4.5% (Table 1). We examined additional family members to the probands with the MC4R mutations, Arg7Cys, Ser19fsdelA, Cys84Arg, and Gly181Asp (Fig. 1). No cosegregation with obesity could be demonstrated for the Ser19fsdelA. Except for one subject, all other carriers of the Arg7Cys variant were either overweight or obese. Carriers of the Cys84Arg variant were all obese, and carriers of the Gly181Asp mutation were all obese except for one subject (Fig. 1). When we examined 106 normal chromosomes for the novel Cys84Arg variant, we did not detect any mutation carriers among normal-weight subjects.
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. No differences in the biochemical variables, birth weight, birth length, and duration of breast-feeding were observed between mutation carriers and noncarriers (data not shown). The Z-scores of BMI, weight, and height at all ages of heterozygous carriers were comparable with noncarriers of MC4R mutations (Fig. 2). The Z-weight at the ages of 1.5 and 3 yr and Z-BMI at 3 yr, respectively, of the homozygous Gly181Asp carrier were above the 95% confidence interval (CI) when compared with heterozygous carriers and noncarriers but not at older ages. However, the Z-height did not exceed the 95% CI except for the height at 5 yr of age (in comparison with heterozygous carriers and noncarriers).
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). Only the homozygous Gly181Asp carrier met the criteria of BED, whereas none of the subjects exhibited the characteristics of Night Eating Syndrome (data not shown).
The four MC4R mutation carriers who underwent a weight reduction program for 6 wk were able to lose body weight (
Z-BMI = 0.95 ± 0.16 kg/m2). This weight loss was comparable with the weight loss of 85 noncarriers ( Z-BMI = 1.06 ± 0.25 kg/m2, p = NS) who also underwent the same 6-wk weight intervention program. The Ser127Leu carrier (also carrier of the Val103Ile variant) undergoing 3 wk of weight reduction regimen succeeded to lose more body weight (Z-BMI = 1.25 kg/m2), compared with the 21 noncarriers who underwent the same 3-wk weight intervention program (Z-BMI = 0.62 ± 0.19 kg/m2). Ten months after the end of the weight reduction regimen, mutation carriers with a high restraint score evaluated by the Eating Inventory succeeded to maintain their weight loss with more success than carriers with a low restraint score (data not shown).
Effect of the mutant Cys84Arg-MC4R on activation of adenylate cyclase
Dose-response curves for [Nle4, D-Phe7](NDP)--MSH and -MSH on COS-7 cells transiently transfected with either the MC4R or the Cys84Arg-MC4R mutant as measured as cAMP accumulation are shown in Fig. 3. In accordance with previous publications (26), the endogenous agonist -MSH stimulated the wild-type MC4R with a relatively low potency of 230 nM but with a high efficacy. In contrast, only a small degree of stimulation was observed with -MSH on the Cys84Arg-MC4R mutant, even at a concentration of 10,000 nM (Fig. 3B). The synthetic, more potent agonist, NDP--MSH, stimulated the wild-type receptor with full efficacy and a potency of 0.53 nM. For this agonist, the Cys84Arg mutation decreased both its potency 10-fold (EC50 = 5.1 nM) and its efficacy 8-fold (Fig. 3C).
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Discussion |
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). Functional studies have shown that Arg7Cys and Ser127Leu mutations alter the -MSH activation of the receptor (27, 28, 29, 30) and that Gly181Asp mutation leads to a loss-of-function receptor (30, 31). This study shows a carrier frequency of 2.4% of MC4R mutations (related to homozygous and heterozygous forms) among obese Czech children and adolescents, which is lower than the reported 5.8% frequency among obese British children (6). The degree of obesity measured as Z-BMI of our cohort (Z-BMI = 4.3 ± 1.7 kg/m2) is, however, comparable with the British cohort (Z-BMI = 4.2 ± 0.8 kg/m2). Previous studies of several populations have shown a great variation in the frequency of MC4R mutations, ranging from 0.5 to 5.8% (4, 6), and the difference in frequency between Czech and British children might be explained by population differences and not by differences in obesity degree of the examined cohorts.
The novel mutation Cys84Arg cosegregated with obesity in three generations (Fig. 1) and was not found in the control subjects. All the carriers of the mutant allele were obese. The Cys-allele is highly conserved among various species (www.ncbi.nlm.nih.gov/blast) and replacement of Cys with Arg is predicted to change the structure of the encoded protein (www.cmpharm.ucsf.edu/
nomi/nnpredict.html). The pathogenic impact of this variant was further supported by the outcome of the functional studies. Importantly, Cys84 is located in the transmembrane (TM) segment II in the same area as an aspartic acid, which is conserved in most seven-TM G protein-coupled receptors. In several receptors this aspartic acid is of crucial importance for the activation through formation of hydrogen bonds with TMVII. Introduction of a positively charged arginine in the proximity may prevent the aspartic acid from the interaction pattern required for full activation (32).
The Arg7Cys mutation has been shown to decrease -MSH signaling of the MC4R (27, 28). However, in our study one of the family members, the proband’s sister, who also carried the Cys-allele and Val103Ile variant was normal weight at the examination (Z-BMI = +0.2 kg/m2) but had a history of obesity at the age of 11 yr (Z-BMI = +1.9 kg/m2). This nonobese phenotype might be due to incomplete penetrance as shown in the study of Dubern et al. (9). A variable impact of functional MC4R variants on body weight has been demonstrated in several studies (5, 9, 14). Furthermore, normal-weight individuals with functionally relevant mutations have been reported in a family based study (11) and very recently in a population-based study (27).
Recently Buono et al. (33) identified the frameshift mutation Ser19fsdelA in one obese subject without performing cosegregation or functional analyses. This mutation introduces a premature stop at codon 51 and thereby alters the NH2 terminus of the MC4R, which is essential for receptor activity (28). In the present study, we identified this frameshift mutation in one very obese child. Interestingly, however, we found different phenotypic expression among the Ser19fsdelA carriers. Thus, the BMI of the mother and grandmother of the proband, both heterozygous mutation carriers, was 20.7 and 23.0 kg/m2, respectively. The proband shared very similar phenotypic expression with the first described frameshift mutation carriers [4 bp del at codon 211 (34), 4 bp ins at codon 244 (35)], and we speculate that the mutation is the cause of obesity in the proband. The identification of the two lean carriers does, however, suggest that other mechanisms might influence the penetrance of this mutation. Thus, the lean mutation carriers might carry other gene variants (leptogenic gene variants) that may interfere with the impact of a defective MC4R. Vaisse et al. (5) identified a family with a frameshift mutation that demonstrated a variable clinical expressivity. This variability was explained by a reduced penetrance of obesity in heterozygous MC4R carriers and a dominant-negative effect (5). Our finding could support a possible dominant-negative effect of some heterozygous MC4R mutations. On the other hand, we can compare the frameshift mutation Ser19fsdelA with the truncated Tyr35stop mutation that has been identified in several studies with a relatively high prevalence. It has been shown that the impact of the mutation is due to haploinsufficiency because the in vitro coexpression studies did not show any evidence of dominant-negative effect (15, 31). It is obvious that to evaluate haploinsufficiency/dominant-negative effects, coexpression of various fluorescently labeled mutant and wild-type receptors in different human cell types and subsequent examination of cell localization with fluorescent microscope are needed.
Among the mutation carriers, only the homozygous Gly181Asp MC4R carrier from unrelated parents had very severe phenotypic expression of obesity already within the first years of life, which is in agreement with previous reports (6, 16). Although the height of the homozygous carrier exceeded the 90th percentile from the age of 3 to 11 yr, we did not find any height differences between all MC4R carriers and the noncarriers during follow-up (Fig. 2). This finding does not support the general notion of an increased linear growth as a characteristic of the MC4R syndrome (6).
Consistent with previous reports of homozygous MC4R mutation carriers, showing that a very early age at onset of obesity is mostly exclusively found in homozygous carriers (6, 10, 36) and obesity-onset in heterozygous MC4R mutation carriers cannot be differentiated from noncarriers, the Gly181Asp homozygous carrier had the earliest onset of obesity. The phenotypic expression and the severity and onset of obesity are also dependent on the type of mutation. Recently Lubrano-Berthelier et al. (16) demonstrated that mutations caused by intracellular retention of the receptor are associated with earlier age onset and greater severity of obesity than other mutations, including those with the complete loss of function.
Hyperinsulinemia has been recognized in some of the MC4R mutation carriers (6). In our cohort, hyperinsulinemia was not characteristic for the MC4R mutation carriers, which is consistent with other reports (9, 14). Even though an increased total bone mineral density has been reported in some of the MC4R mutation carriers (6, 10), the total bone mineral density of all our examined mutation carries was normal, a finding in line with the report by Mergen et al. (13).
Although none of our mutation carriers reported excessive food seeking, we cannot, however, confirm or reject hyperphagia because we have not performed ad libitum energy intake analyses. There has been some debate whether MC4R mutation carriers suffer from BED (37–41). In the current study, only one subject fulfilled the criteria of BED, suggesting that binge eating episodes may not be distinct features of MC4R mutation carriers in the examined cohort. Similar conclusion was reached by Lubrano-Berthelier et al. (16).
This is also the first preliminary report of the response to a weight-reduction regimen of MC4R carriers, compared with noncarriers. Because there were no differences in weight loss between carriers and noncarriers, we assume that mutations in MC4R do not influence the ability to lose body weight in our cohort. Due to the limited number of examined mutation carriers, extended studies of the role of various MC4R mutations in the response to weight reduction regimens are warranted.
In conclusion, we identified MC4R mutations in 2.4% of obese Czech children. One novel missense mutation, Cys84Arg, showed a reduced MC4R activity, cosegregated with obesity and was not identified in 106 control chromosomes. None of the mutation carriers fulfilled the MC4R syndrome criteria of early-onset obesity, increased linear growth, increased bone mineral density, and hyperinsulinemia. In a substudy we showed that that the weight response to a weight loss program was similar in MC4R mutation and wild-type carriers.
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Acknowledgments |
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brady, and Vrchlabí. We especially thank Marianne Stendal for technical assistance and Eva Mattu
ová for secretarial support. |
Footnotes |
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Disclosure Information: All authors have nothing to declare.
First Published Online June 19, 2007
Abbreviations: BED, Binge eating disorder; BMI, body mass index; CI, confidence interval; MC4R, melanocortin 4 receptor; NDP, [Nle4, D-Phe7]; TM, transmembrane.
Received February 15, 2007.
Accepted June 8, 2007.
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References |
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-melanocyte-stimulating hormone genes in severely obese children. J Pediatr 139:204–209[CrossRef][Medline]
ring A, Geller F, Lwel H, Wichmann H-E, Illig T, Hebebrand J, Kronenberg F; the KORA Group 2005 Association of the 103I MC4R allele with decreased body mass in 7937 participants of two population based surveys. J Med Genet 42:e21.This article has been cited by other articles:
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  C. Mohan and A. K. Agarwal Melanocortin-4-Receptor Autoantibodies: A New Player in Obesity J. Clin. Endocrinol. Metab., March 1, 2009; 94(3): 757 - 759. [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
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30 kg/m2; for children BMI > 97th percentile); half-filled symbols denote overweight (for adults BMI = 25–30 kg/m2; for children BMI = 85th to 97th percentile according to the national references). Arrows indicate the probands. N, Normal allele; M, mutant allele; ?, unavailable information. Genotyping is followed by age (years), BMI (kilograms per square meter), and total bone mineral density (grams per square centimeter) per serum insulin (milliinternational units per liter, range 2.6–24.9) for subjects younger than 18 yr Z-score of BMI is included.
