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REVIEW
Genetics of obesity
Rabah M. Shawky
a,b,
*, Doaa I. Sadik
b
a
Pediatrics Department, Faculty of Medicine, Ain Shams University, Egypt
b
Medical Genetics Centre, Ain Shams University, Cairo, Egypt
Received 15 May 2011; accepted 30 August 2011
Available online 9 December 2011
KEYWORDS
Obesity;
Body weight regulation;
Obesity syndromes
Abstract There is now widespread recognition that the continuing increase in the prevalence of
obesity seen in many countries is likely to have major adverse effects on public health. The National
Center for Health Statistics reports that 61% of adults in the United States are overweight and 26%
are obese. Also The National Health and Nutrition Examination Survey IV, 1999–2002, documents
that 16% of children are overweight and 31% are at risk of becoming overweight or are already
overweight, representing nearly a 300% increase since the 1960s. The genetic influences are likely
to be particularly powerful in people with severe and early-onset obesity, the group is most likely
to suffer adverse clinical consequences. In this review we will discuss the Genetics of body weight
regulation including genes encoding factors regulating food/energy intake, genes encoding factors
implicated in energy expenditure, and genes encoding factors implicated in adipogenesis as well
as syndromic forms of obesity.
Ó2012 Ain Shams University. Production and hosting by Elsevier B.V. All rights reserved.
*Corresponding author at: Medical Genetics Center, Ain Shams
University, Cairo, Egypt. Tel.: +20 2 26859398.
E-mail addresses: shawkyrabah@yahoo.com (R.M. Shawky),
doaadoaaibrahim@yahoo.com (D.I. Sadik).
1110-8630 Ó2012 Ain Shams University. Production and hosting by
Elsevier B.V. All rights reserved.
Peer review under responsibility of Ain Shams University.
doi:10.1016/j.ejmhg.2011.08.005
Production and hosting by Elsevier
The Egyptian Journal of Medical Human Genetics (2012) 13, 11–17
Ain Shams University
The Egyptian Journal of Medical Human Genetics
www.ejmhg.eg.net
www.sciencedirect.com
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2. Genetics of body weight regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.1. Genes encoding factors regulating food/energy intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.1.1. Mutations in genes encoding leptin and its receptors (LEP, LEPR). . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.1.2. Mutations in proopiomelanocortin (POMC) gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.1.3. Mutations in melanocortin 4 receptor (MC4R) gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.1.4. Mutations in proprotein convertase 1 (PC1) gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.1.5. Mutations in neuropeptide Y (NPY) gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.1.6. Mutations in ghrelin receptor gene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.1.7. Mutations in genes related to food preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.2. Genes encoding factors implicated in energy expenditure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.2.1. Mutations in b2-adrenoceptor gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.2.2. Mutations in b3-adrenoceptor gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.2.3. Mutations in b1-adrenoceptor gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.2.4. Mutations in uncoupling proteins (UCPs) gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.3. Genes encoding factors implicated in adipogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3. Syndromic forms of obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.1. Monogenic human obesity: pleiotropic syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.1.1. Bardet-Biedl syndrome (BBS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.1.2. Albright’s hereditary osteodystrophy syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.1.3. Borjeson, Forssman and Lehmann syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.1.4. Cohen syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.1.5. Alstro
¨m syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.1.6. Fragile X syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.1.7. Ulnar-mammary syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.1.8. Simpson-Golabi-Behmel, type 2 (SGBS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.1.9. Wilson–Turner syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.1.10. Mehmo syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.2. Obesity syndromes due to chromosomal rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.2.1. Prader-Willi syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.2.2. Sim-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3.2.3. WAGR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1. Introduction
There is now widespread recognition that the continuing
increase in the prevalence of obesity seen in many countries
is likely to have major adverse effects on public health [1,2].
Obesity in children is defined as a body mass index (BMI) at
or above the 95th percentile for children of the same age and
sex based on the Centers for Disease Control and Prevention
(CDC) growth charts for children in the United States [3].
With over 1 billion people now overweight or obese [4], the
World Health Organization has proclaimed this to be a global
epidemic. Particularly alarming is the explosion of childhood
obesity. The National Health and Nutrition Examination
Survey (NHANES) IV, 1999–2002, documents that 16% of
children are overweight and 31% are at risk for becoming
overweight or are already overweight, representing a nearly
300% increase since the 1960s and a 45% increase since the
last complete NHANES survey for 1988–1994 [5].
In the search for the environmental drivers of this epidemi-
ological phenomenon, there is some danger that we may
overlook the critical importance of inherited factors in the
determination of interindividual differences in fat mass. The
identification of such factors is of great clinical, as well as
theoretical importance for a number of reasons. Firstly, genet-
ic influences are likely to be particularly powerful in people
with severe and early-onset obesity, the group is most likely
to suffer adverse clinical consequences [6] (Fig. 1). Secondly,
the use of genetics to identify critical molecular components
Genetics of obesity
Non-syndromic Syndromes
Pleiotropic
syndromes
Chromosomal
rearrangement
Monogenic
obesity
Polygenic
obesity
ADRB1, ADRB2,
ADRB3
UCP1, UCP2, UCP3
LEP, LEPR, POMC,
MC4R, PC1, NPY,
SIM1
Figure 1 Genetics of obesity.
12 R.M. Shawky, D.I. Sadik
of the human control system for energy homoeostasis may
help to target safe and specific drug development. Finally, it
is known that diet and exercise programs, while frequently
effective in inducing weight loss, rarely maintain this. It is very
likely that the genetic makeup of an individual may influence
his/her response to particular measures. Ultimately, it should
be possible to identify genetic subgroups of subjects who might
be particularly responsive or resistant to specific environmen-
tal modulations [7].
Twin studies suggest a heritability of fat mass of between
40% and 70% with a concordance of 0.7–0.9 between mono-
zygotic twins compared with 0.35–0.45 between dizygotic twins
[8,9]. Correlation of monozygotic twins reared apart is virtu-
ally a direct estimate of the heritability (although monozygotic
twins do share the intrauterine environment, which may con-
tribute to lasting differences in body mass in later life). Esti-
mates vary from 40% to 70%, depending on the age of the
separation of twins and the length of follow-up [10].
2. Genetics of body weight regulation
Body weight regulation and stability depends upon an axis
with three interrelated components: food intake, energy expen-
diture and adipogenesis, although there are still many un-
known features concerning fuel homoeostasis and energy
balance. There are 358 studies on obese humans reporting po-
sitive associations with 113 candidate genes, among them, 18
genes are supported by at least five positive studies [6].
2.1. Genes encoding factors regulating food/energy intake
It was generally accepted that hypothalamic and brain stem
centres are involved in the regulation of food intake and en-
ergy balance but information on the relevant regulatory fac-
tors and their genes was scarce until the last decade [1].
Insulin remained the only candidate for the key role in body
weight regulation for a long time.
2.1.1. Mutations in genes encoding leptin and its receptors
(LEP, LEPR)
This cytokine-like peptide mainly expressed by adipocytes is
believed to be a key regulator of fat metabolism and energy in-
take. Leptin is the product of human homologue of mouse ‘ob-
ese’ gene, whose homozygous mutation caused hereditary
obesity in mice (monogenic). Certain areas of the hypothala-
mus are rich in specific receptors binding regulatory peptides
and triggering central regulatory mechanisms. Studies in hu-
mans have failed to find leptin or any other mutant gene to
be the unique ‘obesity gene’. Conversely, multifactorial pat-
terns involving the actions of numerous polymorphic gene
products now look more likely, (proopiomelanocortin
(POMC), MC4R and proprotein convertase 1 (PC1) deficiency
[11]). Congenital human leptin deficiency has been identified in
subjects showing severe early-onset obesity (8 years and 86 kg,
or 2 years and 29 kg) with intense hyperphagia and undetect-
able levels of serum leptin due to a frame-shift mutation in
the ob gene (deletion G133) in a homozygosis, which resulted
in a truncated protein not secreted [12]. Children with leptin
deficiency had also profound abnormalities in T-cell number
and function consistent with the high rates of infection and
childhood mortality from infections. Leptin therapy in these
subjects has a major effect on appetite with normalisation of
hyperphagia and reductions in body weight. Leptin receptor-
deficient subjects were also found, with the phenotype being
similar to those with leptin deficiency. The birth weight was
normal, but a rapid weight gain was seen in the first months
of life, with severe hyperphagia and aggressive behaviour when
food was denied [11,12]. Basal temperature and resting meta-
bolic rate were normal and they were normoglycemic with
mildly elevated plasma insulin. They also had mild growth
retardation and impaired basal and stimulated growth hor-
mone secretion [12].
2.1.2. Mutations in proopiomelanocortin (POMC) gene
Homozygous and heterozygous subjects for mutations in
POMC have been found. In neonatal life these subjects showed
adrenocorticotropic hormone (ACTH) deficiency (the POMC
gene encoded ACTH and other peptides), the children have
red hair and pale skin due to the lack of melanocyte-stimulat-
ing hormone (MSH) action at the melanocortin-1 receptors in
skin and hair follicles [12]. The POMC deficiency is associated
with hyperphagia and early-onset obesity due to the lack of
activation of the melanocortin-4 receptor.
2.1.3. Mutations in melanocortin 4 receptor (MC4R) gene
Since 1998 many groups have reported at least 70 mutations in
MC4R that were associated with early onset obesity [13,14].
Other clinical features of MC4R mutation carriers are hyper-
phagia, accelerated linear growth in children and marked
increase in bone mineral density. Probands with homozygous
MC4R mutations show more severe obesity than their hetero-
zygous relatives; thus, the mode of inheritance is codominant
[12]. Severe obesity and early age of onset, may be markers
of MC4R mutations. It has been also shown that pathogenic
MC4R mutations are more prevalent in northern European
populations than in the Mediterranean or even Asian popula-
tions [13]. MC4R mutations have been extensively reported in
French, English, German, American, Italian and Spanish
populations [2,7–10]. It has been estimated that 1–6% of extre-
mely obese individuals harbour functionally relevant MC4R
mutations [7]. Functional analyses of MC4R mutations (mis-
sense, nonsense and frameshift mutations) allow us to classify
them on the basis of their effects on receptor signalling. Muta-
tions that caused intracellular retention of the receptor in vitro
were associated with earlier age of onset and greater severity of
obesity than other mutations [12]. Functional studies showed
that many of the missense mutations also lead to a loss-
of-function of the MC4R [2].
2.1.4. Mutations in proprotein convertase 1 (PC1) gene
Subject carriers of PC1 mutations mainly have severe early-
onset obesity, impaired prohormone processing and hypocort-
isolaemia. Another clinical feature is small intestine
dysfunction, which may result from an erroneous maturation
of propeptides within the PC1-secreting cells along the gut [12].
2.1.5. Mutations in neuropeptide Y (NPY) gene
NPY is released from the arcuate hypothalamic nucleus in fast-
ing or in hypoglycaemia situations, its secretion being inhibited
after food intake. The Leu7Pro polymorphism in the NPY
gene appears to be implicated in lipid metabolism regulation.
Some works reported that carriers of the Pro7 allele had higher
NPY levels and also body fatness [15].
Genetics of obesity 13
2.1.6. Mutations in ghrelin receptor gene
For the ghrelin receptor gene, two SNPs were reported:
Ala204Glu and Phe279Leu, which selectively impair the
constitutive activity of the receptor in humans leading to short
stature and obesity that apparently develop during puberty
[16].
2.1.7. Mutations in genes related to food preferences
The identification of relevant genes related to food prefer-
ences has just started. A novel family of 40–80 human
and rodent G protein-coupled receptors expressed in taste
receptor cells of tongue and palate epithelia has been identi-
fied. Taste 2 receptors (T2Rs) have been shown to function
as bitter taste receptor and T1Rs as putative receptor for
sweet taste. There is no information on polymorphism in
the T1R family genes while some SNPs in T2R have been
reported [17,18]. Rapid progress has been made in this field
to elucidate the genetic mechanism controlling formation of
food preferences.
2.2. Genes encoding factors implicated in energy expenditure
The adaptive thermogenesis in humans is closely related to the
active mobilization of lipids from fat tissues and demands
special interest in relation to obesity. Central neural pathways
responsible for the food intake and energy expenditure
regulation are tightly interconnected. The peripheral transmis-
sion of central commands to the fat stores is mediated by the
sympathetic nervous system. The b-adrenoceptor gene families
(ADRB2, ADRB3, ADRB1) are intensively studied candidate
genes in the obesity field for their participation in energy
expenditure regulation.
2.2.1. Mutations in b2-adrenoceptor gene
The b2-adrenergic receptor gene (ADRB2) encodes a major
lipolytic receptor protein in human fat cells. Two common
polymorphisms of the ADRB2 gene, characterised by an
amino acid replacement of arginine by glycine in codon 16
(Arg16Gly) and glutamine by glutamic acid in codon 27
(Gln27Glu), have been explored in several diseases such as
hypertension and obesity [19–23]. A relationship between
the Arg16Gly polymorphism and an altered function of
the ADBR2 has been reported leading to decreased agonist
sensitivity. Meanwhile, the Gln27Glu variant was also found
to be linked to obesity in some populations. In men, the
27Glu allele has been associated with increased BMI and
subcutaneous fat and with elevated leptin and triglyceride
levels, while in women, the 27Glu variant was reported to
be linked to increased BMI, body fat mass and waist to
hip ratio [23]. However, other studies in Caucasians (Danish
men, Austrian women and German subjects) found no asso-
ciation between the Gln27Glu variant of the ADRB2 gene
and obesity [24].
2.2.2. Mutations in b3-adrenoceptor gene
The b3-adrenergic receptor (ADRB3) protein plays a role in
adipocyte metabolism. It mediates the rate of lipolysis in re-
sponse to catecholamines and their agonists which have poten-
tial anti-diabetes and anti-obesity properties [25,26].A
common polymorphism in this gene, characterised by an ami-
no acid replacement of tryptophan by arginine at position 64
(Trp64Arg), has been identified and may be linked to lower
lipolytic activity and account for lipid accumulation in the adi-
pose tissue [27]. This polymorphism has been associated with
abdominal/visceral fat obesity in several populations such as
Caucasians and Japanese subjects. Similarly, several studies
carried out among Mexican American, Japanese and Cauca-
sian women have shown that carriers of the Arg allele had a
higher BMI and lower reduction in visceral fat after weight
loss [27]. Some authors, however, failed to reproduce the find-
ing on b-adrenoceptors gene variants and further confirmation
is required.
2.2.3. Mutations in b1-adrenoceptor gene
ADRB1 is considered a potential candidate gene for obesity
because of its role in catecholamine-induced energy homoeo-
stasis. Stimulation of ADRB1, a member of G-protein-coupled
receptors, mediates energy expenditure and lipolysis in adipose
tissue [28,29].
2.2.4. Mutations in uncoupling proteins (UCPs) gene
Uncoupling proteins (UCPs) are involved in the modulation
of heat-generating uncoupled respiration at the mitochon-
drial level. They represent a family of carrier proteins local-
ised in the inner layer of mitochondrial membranes [26].
There are different members: UCP1, mostly expressed in
brown adipose tissue, and has a role in thermogenesis,
UCP2 is ubiquitously present in any tissue and UCP3 is
mainly expressed in skeletal muscle and brown adipose tis-
sue. UCP1, UCP2 mediate mitochondrial proton leak releas-
ing energy stores as heat and thereby affecting energy
metabolism efficiency [26]. The actual functions for UCP3
proteins are still under investigation. It has been proposed
that uncoupling proteins act as regulators of energy metab-
olism. They are fatty acid transmembrane transporters in the
mitochondria facilitating proton exchange [26]. UCP2 and
UCP3 are considered as candidate genes for obesity, given
their function in the regulation of fuel metabolism. Several
UCP2 gene variants have been described: a G/A mutation
in the promoter region 2866G/A, a valine for alanine substi-
tution at amino acid 55 in exon 4 (Ala55Val) and a 45 base
pair insertion/deletion in the untranslated region of exon 8
[26,30]. From the literature, it seems that allele G in the
promoter region of UCP2 increases obesity risk while it af-
fords relative protection for type 2 diabetes [26]. Meanwhile
the Ala55Val polymorphism has shown to be associated
with increased exercise efficiency [31,32].
2.3. Genes encoding factors implicated in adipogenesis
The last group of genes acting in connection with the
peripheral regulation of energy expenditure comprises the
transcription factors leading to adipogenesis and adipocytes
differentiation. The key factor is peroxisome proliferator-
activated receptor g, particularly the adipose specific isoform
PPARG2. In a meta-analysis examining the Pro12Ala poly-
morphism in 19 136 subjects, a positive association with
BMI was found [26]. In this study, the frequency of the Ala
allele, similar to other Caucasian populations, was higher in
obese subjects (allelic frequency 0.13) than in controls (0.08),
suggesting that this polymorphism was associated with obesity
[33]. There is also information on the functional role of
PPARG gene variants. Some mutant proteins appear to have
reduced activity [26].
14 R.M. Shawky, D.I. Sadik
3. Syndromic forms of obesity
3.1. Monogenic human obesity: pleiotropic syndromes
There are about 30 Mendelian disorders with obesity as a
clinical feature, often in association with mental retardation,
dysmorphic features and organ specific developmental abnor-
malities (i.e., pleiotropic syndromes) [12,34]. Positional genetic
strategies have led to the recent identification of several differ-
ent causative mutations underlying such syndromes; however,
in most cases the defective gene product is an intracellular pro-
tein that is expressed throughout the body and its function is
unknown. These syndromes include:
3.1.1. Bardet-Biedl syndrome (BBS)
The origin of obesity is more complex in Bardet-Biedl syn-
drome (prevalence of BBS, 1/100 000). It is an autosomal
recessive syndrome characterised by central obesity (75%),
polydactyly, learning disabilities, rod–cone dystrophy, hypo-
gonadism and renal abnormalities. It is a genetically heteroge-
nous disorder that is known to map to at least eight loci, seven
of which have now been identified at the molecular level
(mutations in BBS1–BBS11 genes) [12,34,35].
3.1.2. Albright’s hereditary osteodystrophy syndrome
Albright’s hereditary osteodystrophy is an autosomal domi-
nant disorder due to mutations in GNASI, which encodes
for a-subunit of the stimulatory G protein (Gs a). Maternal
transmission of GNASI mutations leads to Albright’s heredi-
tary osteodystrophy (obesity, short stature, round facies, ecto-
pic tissue ossification) plus resistance to several hormones,
such as parathyroid hormone which activate Gs in their target
tissues, while paternal transmission leads only to pseudo-
hypoparathyroidism [12,34].
3.1.3. Borjeson, Forssman and Lehmann syndrome
Borjeson, Forssman and Lehmann is described as a syndrome
characterized by obesity, moderate to severe mental retarda-
tion, epilepsy, hypogonadism, and with marked gynaecomas-
tia. Mutations in a novel, widely expressed zinc-finger gene
plant homeodomain (PHD)-like finger (PHF6) have been iden-
tified in affected families [36], although the functional proper-
ties of this protein remain unclear.
3.1.4. Cohen syndrome
Cohen syndrome is an autosomal recessive disorder charac-
terized by obesity, mental retardation, microcephaly, promi-
nent upper central incisors and progressive retinochoroidal
dystrophy that is over-represented in the Finnish population,
although cases have been reported worldwide [37]. The ge-
netic locus for Cohen syndrome was mapped to chromo-
some 8q, and a novel gene, COH1, in this locus was
shown to carry mutations in many patients from different
ethnic groups [38].
3.1.5. Alstro
¨m syndrome
Alstro
¨m syndrome is another autosomal recessive disorder
that is characterized by childhood obesity associated with
hyperinsulinaemia, chronic hyperglycaemia and neurosensory
deficits [39]. Subsets of affected individuals present with
additional features such as dilated cardiomyopathy, hepatic
dysfunction, hypothyroidism, male hypogonadism, short
stature and mild to moderate developmental delay [40].
Mutations in a single gene, ALMS1, have been found to
be responsible for all cases of Alstro
¨m syndrome so far
characterized [41]. The ALMS1 protein has no signal se-
quences or transmembrane regions, suggesting an intracellu-
lar localization.
3.1.6. Fragile X syndrome
Fragile X syndrome is characterized by moderate to severe
mental retardation, macroorchidism, large ears, macroceph-
aly, prominent jaw (mandibular prognathism), high-pitched
jocular speech and mild obesity. In 1991, the molecular clon-
ing of the fragile X locus revealed unstable expansions of a
CGG trinucleotide repeat located in the FMR1 (fragile X
mental retardation) gene [42]. The CGG repeat is polymor-
phic in normal population, with alleles of 6 to about 50
CGGs. Large expansions of the repeat (from 230 to >1000
CGGs) are seen in affected patients, with moderate expan-
sions (from 60 to about 200 CGGs) that are unmethylated
are found in normal transmitting males and in the majority
of clinically normal carrier females. Although the exact func-
tion of FMR protein is not known, it may play a role in the
regulation of transport, stability or translation of some mes-
senger RNAs [43].
3.1.7. Ulnar-mammary syndrome
This syndrome characterized by ulnar defects, delayed pub-
erty, and hypoplastic nipples, is due to defect in the gene
TBX3 located in 12q24.1 [44]
3.1.8. Simpson-Golabi-Behmel, type 2 (SGBS)
It is an X-linked overgrowth syndrome with associated visceral
and skeletal abnormalities. Alterations in the glypican-3 gene
(GPC3), which is located on Xq26, have been implicated in
the aetiology of relatively milder cases of this disorder. Not
all individuals with SGBS have demonstrated disruptions of
the GPC3 locus, which raises the possibility that other loci
on the X chromosome could be responsible for some cases of
this syndrome [45].
3.1.9. Wilson–Turner syndrome
This syndrome characterized by X-linked mental retardation
(XLMR), obesity, gynaecomastia, speech difficulties, emo-
tional lability, tapering fingers, and small feet. [46].
3.1.10. Mehmo syndrome
MEHMO (Mental retardation, Epileptic seizures, Hypogeni-
talism, Microcephaly and Obesity) is an X-linked disorder
characterised by mental retardation, epileptic seizures, hypo-
genitalism, microcephaly and obesity. It was recently assigned
to the locus Xp21.1-p22.13 [47].
3.2. Obesity syndromes due to chromosomal rearrangements
3.2.1. Prader-Willi syndrome
The most frequent syndrome is the Prader-Willi syndrome with
a prevalence of about one in 25 000 births and a population prev-
alence of one in 50 000 [48], and is characterised by obesity,
hyperphagia, hypotonia, mental retardation, short stature and
hypogonadiotropic hypogonadism. It is usually caused by lack
of the paternal segment 15q11.2-q12, either through deletion
Genetics of obesity 15
of the paternal critical segment (75%) or through loss of the en-
tire paternal chromosome 15 with the presence of two maternal
homologues in 22% of patients (uniparental maternal disomy).
One suggested mediator of the obesity phenotype is ghrelin, the
stomach-secreted peptide that increases appetite by interacting
with POMC/CART (cocaine- and amphetamine-regulated tran-
script) and NPY hypothalamic neurons whose levels are high in
Prader-Willi syndrome patients.
3.2.2. Sim-1
A girl has been reported with hyperphagia and early-onset
obesity and a balanced translocation between 1p22.1 and
6q16.2, which would be predicted to disrupt the SIM-1 gene
on 6q. The Drosophila single-minded (sim) gene is a regulator
of neurogenesis, and in mouse Sim-1 is expressed in the devel-
oping central nervous system, and is essential for formation of
the supraoptic and paraventricular (PVN) nuclei which express
the melanocortin-4 receptor. Mice heterozygous for loss-
of-function mutations in Sim-1 are obese [48,49]. In humans,
deletion or disruption of the SIM1 region results in either
‘Prader-Willi-like’ phenotype or an early-onset obesity linked
to hyperphagia. A number of patients with obesity, hypotonia
and developmental delay in association with interstitial chro-
mosome 6q deletions have been described [50], although
whether this syndrome can be attributed to SIM-1 is unclear.
3.2.3. WAGR
The WAGR syndrome (Wilms tumour, anorexia, ambiguous
genitalia and mental retardation) is one of the best-studied
contiguous gene syndromes associated with chromosomal
deletions at 11p13, the location of the WT1 gene. [51]. Some
patients with WAGR syndrome and obesity have been
reported with the deletions of chromosome 11p14-p12 [52].
In conclusion, obesity is a complex phenotype, and the
assessment of obese patients should be directed at identifying
genetic conditions so that appropriate genetic counselling
and in some cases treatment can be instituted. An increasing
number of genes linked to human obesity are being identified.
This knowledge will increase our understanding of the causes
of obesity and the ways in which children respond to their
environments and become obese.
Conflict of interest
The author declares that there is no conflict of interest
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Genetics of obesity 17
