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I Sadaf Farooqi

Publications and source records attributed to I Sadaf Farooqi.

At least 19 recordsLinked to original sources
PubMed2007

Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.

BACKGROUND: A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined. METHODS: We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives. RESULTS: Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. CONCLUSIONS: The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.

Adult↗
PubMed2006

Molecular genetic analysis of normosmic hypogonadotropic hypogonadism in a Turkish population: identification and detailed functional characterization of a novel mutation in the gonadotropin-releasing hormone receptor gene.

BACKGROUND/AIMS: Currently known mutations account for less than 15% of cases with normosmic hypogonadotropic hypogonadism (nIHH). The objective of the study was to identify novel hereditary associations in the pathogenesis of nIHH. METHODS: We investigated 26 Turkish patients with nIHH (21 males and 5 females) from 22 families. The coding regions of the GnRH receptor, GnRH1, GPR54, and KISS1 genes were directly sequenced. RESULTS: In two sisters, a novel homozygous missense mutation, R139C, located in the conserved DRS motif at the junction of the third transmembrane and the second intracellular loop of the GnRH receptor was identified. The R139C mutation almost completely abolished plasma membrane expression while having little effect on GnRH-binding affinity. The mutant receptor expression was rescued by a membrane-permeant, non-peptide GnRH receptor antagonist IN3. CONCLUSIONS: Consistent with the previous studies we were able to find mutations in only 7.6% of a well-defined group of patients with nIHH, which further suggests that yet unidentified genetic associations to explain nIHH exist.

Adolescent↗
PubMed2006

Genetics of obesity.

Considerable attention is currently being paid to the secular changes in food intake and physical activity that underlie the increase in the prevalence of obesity that is apparent in many societies. While this is laudable it would be unwise to view these environmental factors in isolation from the biological factors that normally control body weight and composition and the compelling evidence that inter-individual differences in susceptibility to obesity have strong genetic determinants. This is particularly important, as it is only in the past decade that we have begun to obtain substantive information regarding the molecular constituents of pathways controlling mammalian energy balance and therefore, for the first time, are in a position to achieve a better mechanistic understanding of this disease. Population-based association and linkage studies have highlighted a number of loci at which genetic variation is associated with obesity and related phenotypes and the identification and characterization of monogenic obesity syndromes has been particularly fruitful. While there is widespread acceptance that hereditary factors might predispose to human obesity, it is frequently assumed that such factors would influence metabolic rate or the selective partitioning of excess calories into fat. However, it is notable that, thus far, all monogenic defects causing human obesity actually disrupt hypothalamic pathways and have a profound effect on satiety and food intake. To conclude, the evidence we have to date suggests that the major impact of genes on human obesity is just as likely (or perhaps more likely) to directly impact on hunger, satiety and food intake rather than metabolic rate or nutrient partitioning. At the risk of oversimplification, it seems that from an aetiological/genetic standpoint, human obesity appears less a metabolic than a neuro-behavioural disease.

Adiposity↗
PubMed2006

Sequence variants in the melatonin-related receptor gene (GPR50) associate with circulating triglyceride and HDL levels.

The gene encoding the melatonin-related receptor (GPR50) is highly expressed within hypothalamic nuclei concerned with the control of body weight and metabolism. We screened GPR50 for mutations in an obese cohort and identified an insertion of four amino acid residues (TTGH) at position 501, two common coding polymorphisms (T528A and V602I), and one noncoding polymorphism (C-16X2GPR50T). Single-nucleotide polymorphisms were then typed in 500 English Caucasian subjects, and associations were sought to intermediate obesity phenotypes. Although no association was seen with body mass index, carriers of two copies of the mutant allele at C-16X2GPR50T, Ins501Del, and A1582G had significantly higher fasting circulating triglyceride levels (P < 0.05). In a separate set of 585 subjects, the associations were replicated, with statistically significant effects of similar magnitude and direction. The association of C-16X2GPR50T with fasting triglycerides was highly significant (P < 0.001). In addition, a significant association between C-16X2GPR50T and circulating HDL levels was observed in the combined population, with C-16X2GPR50T carriers having significantly lower circulating HDL-cholesterol levels (1.39 mM) than wild-type subjects (1.47 mM) (P < 0.01). These findings suggest a previously unexpected role for this orphan receptor in the regulation of lipid metabolism that warrants further investigation.

Amino Acid Sequence↗
PubMed2006

A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance.

The melanocortin-4 receptor (MC4R) plays a critical role in the control of energy balance. Of its two pro-opiomelanocortin (POMC)-derived ligands, alpha- and beta-MSH, the majority of attention has focused on alpha-MSH, partly reflecting the absence of beta-MSH in rodents. We screened the POMC gene in 538 patients with severe, early-onset obesity and identified five unrelated probands who were heterozygous for a rare missense variant in the region encoding beta-MSH, Tyr221Cys. This frequency was significantly increased (p < 0.001) compared to the general UK Caucasian population and the variant cosegregated with obesity/overweight in affected family members. Compared to wild-type beta-MSH, the variant peptide was impaired in its ability to bind to and activate signaling from the MC4R. Obese children carrying the Tyr221Cys variant were hyperphagic and showed increased linear growth, both of which are features of MC4R deficiency. These studies support a role for beta-MSH in the control of human energy homeostasis.

Child, Preschool↗
PubMed2006

The severely obese patient--a genetic work-up.

BACKGROUND: A 6-year-old boy weighing 53 kg was referred to a specialist unit for investigation of severe obesity. Parental reports of persistent severe hyperphagia and food-seeking behavior from a very early age raised the possibility of a genetic obesity syndrome. The family history was suggestive of a dominantly inherited condition, because the boy's father had been hospitalized in early childhood for the management of his obesity. INVESTIGATIONS: Physical examination of the patient, and his mother and father, measurement of serum leptin and insulin levels, lipid profile and thyroid function tests, karyotyping and molecular genetic testing. DIAGNOSIS: The patient was heterozygous for a missense mutation in the melanocortin 4 receptor gene, which segregated in a dominant manner in this family. MANAGEMENT: Counseling for genetic studies in the family and advice regarding dietary management.

Body Mass Index↗
PubMed2006

A quantitative trait locus on chromosome 18q for physical activity and dietary intake in Hispanic children.

OBJECTIVE: Genetic components of energy homeostasis contributing to childhood obesity are poorly understood. Genome scans were performed to identify chromosomal regions contributing to physical activity and dietary intake traits in Hispanic children participating in the VIVA LA FAMILIA Study. RESEARCH METHODS AND PROCEDURES: We report linkage findings on chromosome 18 for physical activity and dietary intake in 1030 siblings from 319 Hispanic families. Measurements entailed physical activity by accelerometry, dietary intake by two 24-hour recalls, and genetic linkage analyses using SOLAR software. RESULTS: Significant heritabilities were seen for physical activity and dietary intake, ranging from 0.46 to 0.69, except for vigorous activity (h2 = 0.18). Percentage time in sedentary activity mapped to markers D18S1102-D18S64 on chromosome 18 [logarithm of the odds (LOD) score = 4.07], where melanocortin 4 receptor gene (MC4R) resides. Quantitative trait loci (QTLs) for total activity counts, percentage time in light or in moderate activity, and carbohydrate intake and percentage of energy intake from carbohydrates were detected in the same region (LOD = 2.28, 2.79, 2.2, 1.84, and 1.51, respectively). A novel loss of function mutation in MC4R (G55V) was detected in six obese relatives, but not in the rest of the cohort. Removal of these MC4R-deficient subjects from the analysis reduced the LOD score for sedentary activity to 3.94. DISCUSSION: Given its role in the regulation of food intake and energy expenditure, MC4R is a strong positional candidate gene for the QTL on chromosome 18 detected for physical activity and dietary intake in Hispanic children.

Adolescent↗
PubMed2006

Heterozygosity for a POMC-null mutation and increased obesity risk in humans.

Congenital deficiency of proopiomelanocortin (POMC) results in a syndrome of hypoadrenalism, severe obesity, and altered skin and hair pigmentation. The concept that subtle variation in POMC expression and/or function might contribute to common obesity is suggested by studies reporting linkage of obesity-related traits to a locus on chromosome 2p22 encompassing the POMC gene. We identified a novel homozygous frameshift (C6906del) mutation in POMC in a child of Turkish origin with severe obesity and hypoadrenalism. This mutation would be predicted to lead to the loss of all POMC-derived peptides. The availability of a large extended pedigree provided the opportunity to address whether loss of one copy of the POMC gene was sufficient to alter obesity risk. Twelve relatives were heterozygous for the mutation and 7 were wild type. Of the heterozygotes, 11 of 12 heterozygotes were obese or overweight compared with only 1 of 7 of the wild-type relatives. The mean BMI SD score was 1.7 +/- 0.5 in heterozygotes and 0.4 +/- 0.4 in the wild-type relatives. Parametric linkage analysis of the trait "overweight" provided statistically significant evidence of linkage with this locus, with a maximum "location score" (comparable with multipoint logarithm of odds scores) of 3.191. We conclude that loss of one copy of the POMC gene predisposes to obesity in humans. Thus, genetic variants having relatively subtle effects on POMC expression and function could influence susceptibility to obesity.

Adult↗
PubMed2006

Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene.

The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the 5' end of the BDNF gene. The patient's genomic DNA was heterozygous for a common coding polymorphism in BDNF, but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared with age- and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyperactivity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior.

Adult↗
PubMed2005

Genetic and hereditary aspects of childhood obesity.

Genetic factors are involved in the regulation of body weight and in determining individual responses to environmental factors such as diet and exercise. The identification and characterization of monogenic obesity syndromes have led to an improved understanding of the precise nature of the inherited component of severe obesity and has had undoubted medical benefits, whilst helping to dispel the notion that obesity represents an individual defect in behaviour with no biological basis. For individuals at highest risk of the complications of severe obesity, such findings provide a starting point for providing more rational mechanism-based therapies, as has successfully been achieved for one disorder, congenital leptin deficiency.

Bardet-Biedl Syndrome↗
PubMed2005

Leptin predicts a worsening of the features of the metabolic syndrome independently of obesity.

OBJECTIVE: The term metabolic syndrome (MS) describes a cluster of cardiovascular risk factors including dyslipidemia, glucose intolerance, insulin resistance, and hypertension. Obesity increases the risk of MS, but as obesity is neither necessary nor sufficient to cause the syndrome, there is considerable interest in identifying obesity-independent pathways. One such pathway may involve the actions of the adipokine leptin, which is associated cross-sectionally with MS and prospectively with coronary heart disease and stroke, independently of obesity. Our goal was to test the hypothesis that leptin predicts the development of the features of MS independently of obesity. RESEARCH METHODS AND PROCEDURES: This study used a prospective population-based cohort of 748 middle-aged whites in whom baseline measures of leptin and repeated measurement of the subcomponents of the MS at 5 and 10 years were available. The features of the MS were characterized as five factors (obesity, dyslipidemia, elevated blood pressure, glucose intolerance, and insulin resistance), which were combined to create an MS summary score. RESULTS: Baseline leptin significantly predicted the development of obesity (p = 0.001) and, after adjustment for BMI, development of glucose intolerance (p = 0.016) and insulin resistance (p < 0.0001). Leptin levels did not independently predict a change in lipids or blood pressure. Leptin levels significantly predicted the development of the MS (p = 0.036), independently of baseline BMI. DISCUSSION: Leptin predicts the development of the MS independently of baseline obesity. This association is specifically related to the development of glucose intolerance and insulin resistance. The extent to which these relationships are explained through residual confounding by obesity remains to be determined.

Adult↗
PubMed2005

Evaluation of Prader-Willi Syndrome gene MAGEL2 in severe childhood-onset obesity.

MAGEL2 is one of the five genes inactivated in Prader-Willi Syndrome, a neurodevelopmental chromosome microdeletion disorder modified by genomic imprinting. By early childhood, individuals with Prader-Willi Syndrome exhibit hypothalamic dysfunction, including hyperphagia, and become obese in the absence of behavioral intervention. Murine Magel2 is highly expressed in the hypothalamus during development. We screened the MAGEL2 open reading frame for mutations in genomic DNA samples from hyperphagic but non-dysmorphic individuals with severe childhood-onset obesity. Although no mutations likely to affect gene function were identified, we identified three variant alleles. We conclude that severe childhood-onset obesity is not commonly caused by MAGEL2 mutations.

Antigens, Neoplasm↗
PubMed2005

Monogenic obesity in humans.

Until relatively recently, the small number of identifiable inherited human diseases associated with marked obesity were complex, pleiotropic developmental disorders, the molecular basis for which were entirely obscure. The molecular basis for many of these complex syndromes, such as Bardet Beidl syndrome, has been revealed, providing novel insights into processes essential for human hypothalamic function and energy balance. In addition to these discoveries, which were the fruits of positional cloning, the molecular constituents of the signaling pathways responsible for the control of mammalian energy homeostasis have been identified, largely through the study of natural or artificial mutations in mice. We discuss the increasing number of human disorders that result from genetic disruption of the leptin-melanocortin pathways that have been identified. Practical implications of these findings for genetic counseling, prognostication, and even therapy have already emerged.

Adolescent↗
PubMed2004

A de novo mutation affecting human TrkB associated with severe obesity and developmental delay.

An 8-year-old male with a complex developmental syndrome and severe obesity was heterozygous for a de novo missense mutation resulting in a Y722C substitution in the neurotrophin receptor TrkB. This mutation markedly impaired receptor autophosphorylation and signaling to MAP kinase. Mutation of NTRK2, which encodes TrkB, seems to result in a unique human syndrome of hyperphagic obesity. The associated impairment in memory, learning and nociception seen in the proband reflects the crucial role of TrkB in the human nervous system.

Age Factors↗
PubMed2004

Melanin-concentrating hormone receptor mutations and human obesity: functional analysis.

Melanin-concentrating hormone (MCH), a neuropeptide highly expressed in the lateral hypothalamus, has an important role in the regulation of energy balance and body weight in rodents. We examined whether mutations in the two known MCH receptors might be associated with obesity-related phenotypes in humans. Among 106 subjects with severe early onset obesity and a history of hyperphagia, we found two missense variants in MCHR1: Y181H and R248Q. Neither of these was found in 192 normal weight controls. R248Q cosegregated with obesity across two generations; family data were unavailable for Y181H. When expressed in HEK293 cells, R248Q showed no evidence of constitutive activation or ligand hypersensitivity for extracellular signal-regulated kinase phosphorylation. In addition, R248Q showed no enhanced suppression of cAMP generation. Two common single-nucleotide polymorphisms were found to be in linkage disequilibrium: g.-114A>G and c.39C>T. No association between either of these single-nucleotide polymorphisms and obesity-related phenotypes was found among a population cohort of 541 whites. Only two rare noncoding variants were found in MCHR2. In conclusion, mutations in the MCH receptors are not commonly found in humans with severe early onset obesity. Clarification of the relationship of these variants to obesity must await study in other populations and/or in genetically modified mice.

Amino Acid Sequence↗