DNA polymerase δ, whose catalytic subunit is encoded by POLD1, is responsible for lagging-strand DNA synthesis during DNA replication. It carries out this synthesis with high fidelity owing to its ...intrinsic 3'- to 5'-exonuclease activity, which confers proofreading ability. Missense mutations affecting the exonuclease domain of POLD1 have recently been shown to predispose to colorectal and endometrial cancers. Here we report a recurring heterozygous single-codon deletion in POLD1 affecting the polymerase active site that abolishes DNA polymerase activity but only mildly impairs 3'- to 5'-exonuclease activity. This mutation causes a distinct multisystem disorder that includes subcutaneous lipodystrophy, deafness, mandibular hypoplasia and hypogonadism in males. This discovery suggests that perturbing the function of the ubiquitously expressed POLD1 polymerase has unexpectedly tissue-specific effects in humans and argues for an important role for POLD1 function in adipose tissue homeostasis.
Contribution of Variants in the Small Heterodimer Partner Gene to Birthweight, Adiposity, and Insulin Levels
Mutational Analysis and Association Studies in Multiple Populations
Chiao-Chien Connie ...Hung 1 ,
I. Sadaf Farooqi 1 ,
Ken Ong 2 ,
Jian’an Luan 3 ,
Julia M. Keogh 1 ,
Marcus Pembrey 4 ,
Giles S.H. Yeo 1 ,
David Dunger 2 ,
Nicholas J. Wareham 3 and
Stephen O’ Rahilly 1
1 University Departments of Medicine and Clinical Biochemistry, Cambridge Institute for Medical Research, Cambridge, U.K
2 Department of Paediatrics, Addenbrooke’s Hospital, Cambridge, U.K
3 Department of Public Health and Epidemiology, Addenbrooke’s Hospital, Cambridge, U.K
4 Unit of Perinatal and Paediatric Epidemiology, University of Bristol, Bristol, U.K
Abstract
Loss of function mutations in the small heterodimer partner ( SHP ) gene have been reported to cause obesity and increased birth weight. We examined the relation between genetic variation
in SHP and birth weight, adiposity, and insulin levels in three independent populations. The coding regions and 562 bases of the
SHP promoter were screened for mutations in 329 subjects with severe early-onset obesity. Two novel missense mutations, R34G
and R36C, were identified; these were not found in control subjects and did not cosegregate with obesity in family studies.
Two common polymorphisms, G171A and −195CTGAdel, were found in 12 and 16% of subjects, respectively. Within the obese cohort,
G171A and −195CTGAdel carriers had higher and lower birth weights, respectively, than wild-type subjects, the rare homozygotes
for G171A being particularly large at birth. In a U.K. population-based cohort of 1,079 children, the 171A allele was associated
with higher BMI ( P < 0.05) and waist circumference ( P = 0.001). Children carrying the G171A variant had higher 30-min insulin responses to a glucose load ( P = 0.03). In conclusion, although mutations in SHP are not a common cause of severe human obesity, genetic variation in the SHP locus may influence birth weight and have effects on BMI, possibly through effects on insulin secretion.
Footnotes
Address correspondence and reprint requests to Stephen O’Rahilly, University Department of Clinical Biochemistry, Addenbrooke’s
Hospital, Cambridge, CB2 2QQ, U.K. E-mail: sorahill{at}hgmp.mrc.ac.uk .
Received for publication 15 November 2002 and accepted in revised form 30 January 2003.
C.C.H. and I.S.F. contributed equally to this work.
Additional information can be found in an online appendix at http://diabetes.diabetesjournals.org .
ALSPAC, Avon Longitudinal Study of Parents and Children; DHPLC, denaturing high-performance liquid chromatography; GOOS, Genetics
Of Obesity Study; HNF-4α, hepatocyte nuclear factor-4α; MODY, maturity onset diabetes of the young; SDS, standard deviation
score; SHP, small heterodimer partner.
DIABETES
Loss of function mutations in the small heterodimer partner (SHP) gene have been reported to cause obesity and increased birth weight. We examined the relation between genetic variation in SHP and ...birth weight, adiposity, and insulin levels in three independent populations. The coding regions and 562 bases of the SHP promoter were screened for mutations in 329 subjects with severe early-onset obesity. Two novel missense mutations, R34G and R36C, were identified; these were not found in control subjects and did not cosegregate with obesity in family studies. Two common polymorphisms, G171A and -195CTGAdel, were found in 12 and 16% of subjects, respectively. Within the obese cohort, G171A and -195CTGAdel carriers had higher and lower birth weights, respectively, than wild-type subjects, the rare homozygotes for G171A being particularly large at birth. In a U.K. population-based cohort of 1,079 children, the 171A allele was associated with higher BMI (P < 0.05) and waist circumference (P = 0.001). Children carrying the G171A variant had higher 30-min insulin responses to a glucose load (P = 0.03). In conclusion, although mutations in SHP are not a common cause of severe human obesity, genetic variation in the SHP locus may influence birth weight and have effects on BMI, possibly through effects on insulin secretion.
Genetics of Obesity Syndromes Beales, Philip R; Farooqi, I. Sadaf; O'Rahilly, Stephen
2008, 2008-08-29, Letnik:
56
eBook
Obesity is one of the most important contributors to disease throughout the world and an area of great current interest among researchers and clinicians. The genetics of common obesity is complex and ...far from resolved. However, an important view thread through the labyrinth is the study of well-described genetic syndromes (often involving mental retardation and a constellation of other disorders) in which obesity is a major component. By examining the genetic mechanisms of obesity in these syndromes, the authors shed light on the genetics of common obesity. This book is the first in this new area and covers both the molecular and clinical features of the obesity syndromes, providing hard-core information for research and practical guidance for clinicians caring for obesity patients.
Mutations in the insulin receptor gene have been detected in patients with severe insulin resistance, but the absence of insulin receptors has not been recorded. We report a severely insulin ...resistant newborn baby, the offspring of consa-inguineous parents, who was homozygous for a nonsense mutation (Lys 121–Amber) in this gene. Translation of this very truncated N-terminal fragment would not be expected to result in a functional insulin receptor. The infant had all the typical features of the syndrome of leprechaunism. The baby probably represents the null phenotype with respect to the insulin receptor. Because insulin receptors are expressed very early in the developing embryo, the absence of functional insulin receptors is thought to be incompatible with fetal viability: the normal organogenesis in this infant who survived beyond term implies that this assumption is probably incorrect; Lancet 1993;
342: 277–78
Melanocortin receptors and energy homeostasis Coll, Anthony P; Challis, Benjamin G; Yeo, Giles S. H ...
Current opinion in endocrinology & diabetes,
2005-June, 2005-06-00, Letnik:
12, Številka:
3
Journal Article
PURPOSE OF REVIEWThis article highlights new information regarding the physiology of the central melanocortin system and how defects in it contribute to human metabolic disease.
RECENT ...FINDINGSSelective abolition of leptin action on pro-opiomelanocortin neurons causes an obese phenotype, demonstrating that leptin signaling through pro-opiomelanocortin neurons is essential for normal energy homeostasis. Novel roles of leptin are also becoming apparent with evidence that acetylation of α-melanocyte-stimulating hormone into its more biologically activity form is leptin dependent. Leptin can also regulate hepatic glucose fluxes through a central melanocortin-dependent pathway. We review evidence that the brain stem melanocortin system mediates the effects of cholecystokinin, suggesting that the melanocortin system integrates short-term satiety signals as well as long-term adipostatic signals like leptin. The downstream targets of MC4-R are now becoming apparent with melanin-concentrating hormone and brain-derived neurotrophic factor implicated as key ‘second order’ mediators. Evidence from different ethnic groups shows MC4-R mutations to be the most common single gene disorder causing obesity. The functional properties of naturally occurring human mutants suggest the N-terminal domain of the MC4-R may function as a tethered intramolecular ligand, maintaining constitutive receptor activity.
SUMMARYRecent studies have reiterated the critical role the central melanocortin pathway plays in the control of energy balance. Given the public health challenge that obesity presents, the potential attractiveness of the melanocortin system as a therapeutic target only grows as knowledge of its molecular physiology increases.
Background/Aims: Donohue and Rabson-Mendenhall syndrome are rare autosomal recessive disorders caused by mutations in the insulin receptor gene, INSR. Phenotypic features include extreme insulin ...resistance, linear growth retardation, paucity of fat and muscle, and soft tissue overgrowth. The insulin receptor is also expressed in the kidney, where animal data suggest it plays a role in glomerular function and blood pressure (BP) regulation, yet such a role in the human kidney is untested. Patients with biallelic INSR mutations provide a rare opportunity to ascertain its role in man. Methods: Retrospective review of patients with INSR mutations. Data for BP, renal imaging, plasma creatinine and electrolyte levels, as well as urine protein, albumin and calcium excretion were sought from the treating clinicians. Results: From 33 patients with INSR mutations, data were available for 17 patients. Plasma creatinine was low (mean ± SD: 25 ± 9 μmol/l) and mean plasma electrolyte concentrations were within the normal range (n = 13). Systolic BP ranged between the 18th and 91st percentile for age, sex, height and weight (n = 9; mean ± SD: 49 ± 24). Twenty-four-hour urinary calcium data were available from 10 patients and revealed hypercalciuria in all (mean ± SD: 0.32 ± 0.17 mmol/kg/day; normal <0.1). Nephrocalcinosis was present in all patients (n = 17). Urinary albumin excretion (n = 7) ranged from 4.3-122.5 μg/min (mean ± SD: 32.4 ± 41.0 μg/min; normal <20). Conclusions: INSR dysfunction is associated with hypercalciuria and nephrocalcinosis. No other consistent abnormality of renal function was noted. Normotension and stable glomerular function with only moderate proteinuria is in contrast to genetically modified mice who have elevated BP and progressive diabetic nephropathy.
PDF
