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Linkage of an X-chromosome cleft palate gene.

Many congenital malformations, such as cleft palate and neural tube defects, have a multifactorial origin involving both environmental and genetic factors. Conditions such as these may be exclusively monogenic, polygenic or environmental, but in most cases both genetic and environmental factors are involved. This study describes the sub-chromosomal localization of a single gene defect causing cleft palate and ankyloglossia (tongue-tied) in a large Icelandic family. This defect is a model for the analysis of other neural-crest malformations that show a more complex multifactorial inheritance pattern.

Cleft Palate↗
PubMed1988

Evidence against linkage of schizophrenia to markers on chromosome 5 in a northern Swedish pedigree.

Schizophrenia is a severe mental illness with a typically chronic course affecting nearly 1% of the human population. It is generally accepted that genetic factors have an important pathogenic role in a substantial portion of schizophrenia cases; however, despite decades of family studies, there is no agreed-upon mode of inheritance. The discovery of genetic aetiologic factors and resolution of the inheritance pattern(s) will undoubtably emerge from genetic linkage studies. With these objectives in mind, we undertook a linkage project, starting in 1985, in a previously well-documented kindred from north Sweden. Multipoint linkage analyses were used to screen the proximal long arm of chromosome 5 using restriction fragment length polymorphism (RFLP) markers at five loci and the distal long arm using RFLPs at two loci, one of which was the locus for the glucocorticoid receptor. We found strong evidence against linkage between schizophrenia and the seven loci. These results, together with the positive evidence for linkage of schizophrenia with markers in the proximal long arm of chromosome 5 lead us to conclude that the genetic factors underlying schizophrenia are heterogeneous.

Chromosomes, Human, Pair 5↗
PubMed2000

Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance.

The prevalence of type 2 diabetes mellitus is growing worldwide. By the year 2020, 250 million people will be afflicted. Most forms of type 2 diabetes are polygenic with complex inheritance patterns, and penetrance is strongly influenced by environmental factors. The specific genes involved are not yet known, but impaired glucose uptake in skeletal muscle is an early, genetically determined defect that is present in non-diabetic relatives of diabetic subjects. The rate-limiting step in muscle glucose use is the transmembrane transport of glucose mediated by glucose transporter (GLUT) 4 (ref. 4), which is expressed mainly in skeletal muscle, heart and adipose tissue. GLUT4 mediates glucose transport stimulated by insulin and contraction/exercise. The importance of GLUT4 and glucose uptake in muscle, however, was challenged by two recent observations. Whereas heterozygous GLUT4 knockout mice show moderate glucose intolerance, homozygous whole-body GLUT4 knockout (GLUT4-null) mice have only mild perturbations in glucose homeostasis and have growth retardation, depletion of fat stores, cardiac hypertrophy and failure, and a shortened life span. Moreover, muscle-specific inactivation of the insulin receptor results in minimal, if any, change in glucose tolerance. To determine the importance of glucose uptake into muscle for glucose homeostasis, we disrupted GLUT4 selectively in mouse muscles. A profound reduction in basal glucose transport and near-absence of stimulation by insulin or contraction resulted. These mice showed severe insulin resistance and glucose intolerance from an early age. Thus, GLUT4-mediated glucose transport in muscle is essential to the maintenance of normal glucose homeostasis.

Animals↗
PubMed2001

Overexpression of petunia chalcone isomerase in tomato results in fruit containing increased levels of flavonols.

Tomatoes are an excellent source of the carotenoid lycopene, a compound that is thought to be protective against prostate cancer. They also contain small amounts of flavonoids in their peel ( approximately 5-10 mg/kg fresh weight), mainly naringenin chalcone and the flavonol rutin, a quercetin glycoside. Flavonols are very potent antioxidants, and an increasing body of epidemiological data suggests that high flavonoid intake is correlated with a decreased risk for cardiovascular disease. We have upregulated flavonol biosynthesis in the tomato in order to generate fruit with increased antioxidant capacity and a wider range of potential health benefit properties. This involved transformation of tomato with the Petunia chi-a gene encoding chalcone isomerase. Resulting transgenic tomato lines produced an increase of up to 78 fold in fruit peel flavonols, mainly due to an accumulation of rutin. No gross phenotypical differences were observed between high-flavonol transgenic and control lines. The phenotype segregated with the transgene and demonstrated a stable inheritance pattern over four subsequent generations tested thus far. Whole-fruit flavonol levels in the best of these lines are similar to those found in onions, a crop with naturally high levels of flavonol compounds. Processing of high-flavonol tomatoes demonstrated that 65% of flavonols present in the fresh fruit were retained in the processed paste, supporting their potential as raw materials for tomato-based functional food products.

Chalcone↗
PubMed1997

Parental cancer and risk of papillary and follicular thyroid carcinoma.

In a population-based case-control study in the Uppsala-Orebro Health Care Region of Sweden, the histories of cancer among parents of 517 histologically confirmed cases of papillary and follicular carcinoma and of a similar number of sex- and age-matched controls were compared. The parental history of cancer was compiled through information from death certificates and from the nationwide Cancer Register. The incidence of malignancies in a cohort of parents of cases of thyroid cancer was also compared with the incidence in the whole Swedish population. A maternal history of cancer was more common among women with follicular carcinoma than among their controls (OR 2.11, 95% CI 0.96-4.67). Parents of probands with papillary carcinoma had an increased risk of thyroid cancer (OR 4.25, 95% CI 1.16-10.89), and mothers of probands with follicular carcinoma had an increased risk of stomach cancer (OR 3.65, 95% CI 0.99-9.35) compared with the general population. Cancer of the lung, breast, and pancreas were less common than in the general population. Familial cases of thyroid cancer were not limited to the papillary type. An inheritable pattern of carcinogenesis is possible for certain differentiated non-medullary thyroid cancers, but shared environmental exposures may also explain the parent-child associations of cancer in this study.

Adenocarcinoma, Follicular↗
PubMed2001

Autosomal dominant congenital superior oblique palsy.

PURPOSE: We describe a mother and all her offspring with congenital superior oblique palsy (CSOP), and a father and all his sons with unilateral CSOP. We discuss the inheritance pattern in our pedigrees and compare it with previous reports. METHOD: All available family members were examined. The prism cover test was performed. Ocular movements were examined in all positions of gaze and where possible a Hess chart plotted. Lang and TNO stereotests were used to determine the stereo-acuity. The results of these tests combined with the Bielschowsky head tilt test (BHTT) were used to confirm the diagnosis of superior oblique palsy. The condition was classified as congenital if it presented early based on history or the observation of old photographs and in the absence of a causative factor. RESULTS: The affected members of family A consist of a father and his three sons with unilateral CSOP. His daughter had a mild weakness of her left inferior and superior rectus muscle. One of his sons was asymptomatic and only recognised on screening of the family for the study. The affected members of family B consist of a mother and her younger daughter with unilateral CSOP and her older daughter with bilateral CSOP. She had no other children. CONCLUSIONS: Our families demonstrate what is probably an autosomal dominant form of CSOP. It is possible that hereditary CSOP is more common than previously reported.

Adult↗
PubMed1986

IgA synthesis by lymphocytes from patients with IgA nephropathy and their relatives.

To investigate the hypothesis that a predisposition to IgA nephropathy (IgAN) is linked to the major histocompatibility complex (MHC) and associated with poorly regulated IgA synthesis, we performed HLA typing and lymphocyte cultures on patients with IgAN and their relatives. Nineteen of 22 patients had elevated culture supernatant IgA concentrations (620 vs. 154 ng/2 X 10(6) cells, P = 0.007). Supernatant IgG and IgM were normal. No HLA antigen occurred with increased frequency in patients. There was an increased incidence of homozygous null C4 alleles in patients (P less than 0.01). In families, six of 11 mothers, six of 12 fathers, and seven of 15 siblings had elevated supernatant IgA concentrations. There was no segregation of abnormal IgA production with any HLA antigen or parental haplotype. The data confirm elevated in vitro IgA production by lymphocytes from patients with IgAN, but do not support a linkage with the MHC. The increased incidence of homozygous null C4 alleles may result from functional differences in C4 A and B gene products. The familial clustering of elevated IgA production without an obvious inheritance pattern suggest that shared environmental factors may be important in the development of IgAN.

Alleles↗
PubMed1993

Autosomal-dominant polycystic kidney disease in the rat.

Kaspareit-Rittinghausen described a rodent model of inherited polycystic kidney disease (PKD), the Han:SPRD rat [1, 2], in which heterozygotes develop renal cysts and renal failure (in males) over several months, whereas homozygous animals develop rapidly progressive renal enlargement that leads to death in a few weeks. In this study, we examined selected elements of the pathogenesis of this disease in heterozygotes and homozygotes from birth to advanced disease. Heterozygous male rats developed slowly progressive renal cystic disease with interstitial fibrosis and azotemia seen by six months of age. Female heterozygotes developed slowly progressive renal cystic disease, but did not develop interstitial fibrosis or azotemia. Epithelial cells lining cyst cavities showed various degrees of morphologic immaturity. Cyst walls also developed basement membrane thickening, especially in areas of cellular immaturity, suggesting an interrelationship between this basement membrane thickening and cellular dedifferentiation. Thickened basement membranes were associated with increased immunoreactivity for type IV collagen, laminin, and fibronectin. Homozygous rats developed massive renal enlargement, marked azotemia, and died near three weeks of age. Renal c-myc proto-oncogene expression was elevated in homozygous cystic infants and in adult heterozygotes. In situ hybridization showed high levels of c-myc mRNA in cyst epithelia, suggesting abnormal regulation of cellular proliferation in the cells lining cysts, as seen in other models of PKD. The Han:SPRD rat is the only well-documented animal model of inherited PKD with an autosomal-dominant inheritance pattern and appears to have several features which resemble human ADPKD.

Animals↗
PubMed2005

A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk.

The identification of common variants that contribute to the genesis of human inherited disorders remains a significant challenge. Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations in the receptor tyrosine kinase RET contribute to risk in combination with mutations at other genes. We have used family-based association studies to identify a disease interval, and integrated this with comparative and functional genomic analysis to prioritize conserved and functional elements within which mutations can be sought. We now show that a common non-coding RET variant within a conserved enhancer-like sequence in intron 1 is significantly associated with HSCR susceptibility and makes a 20-fold greater contribution to risk than rare alleles do. This mutation reduces in vitro enhancer activity markedly, has low penetrance, has different genetic effects in males and females, and explains several features of the complex inheritance pattern of HSCR. Thus, common low-penetrance variants, identified by association studies, can underlie both common and rare diseases.

Animals↗
PubMed1993

Microsatellite mapping of a gene affecting horn development in Bos taurus.

The presence or absence of horns in Bos taurus is thought to be under the genetic control of the autosomal polled locus, characterized by two alleles: P dominant over p, and causing the polled or hornless phenotype. We have demonstrated genetic linkage between the polled locus and two microsatellite markers, GMPOLL-1 and GMPOLL-2, and have assigned the corresponding linkage group to bovine chromosome 1. This confirms the existence of the postulated polled locus and the hypothesized inheritance pattern. It will allow marker assisted selection for the polledness trait in breeding programs and is a first step towards positional cloning and molecular study of a gene that has been subjected to both natural and artificial selection.

Alleles↗
PubMed1994

A missense mutation in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor in the spasmodic mouse.

Hereditary hyperekplexia, an autosomal dominant neurologic disorder characterized by an exaggerated startle reflex and neonatal hypertonia, can be caused by mutations in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor (GLRA1). Spasmodic (spd), a recessive neurologic mouse mutant, resembles hyperekplexia phenotypically, and the two disease loci map to homologous chromosomal regions. Here we describe a Glra1 missense mutation in spd that results in reduced agonist sensitivity in glycine receptors expressed in vitro. We conclude that spd is a murine homologue of hyperekplexia and that mutations in GLRA1/Glra1 can produce syndromes with different inheritance patterns.

Amino Acid Sequence↗
PubMed1993

Effect of the myotonic dystrophy (DM) mutation on mRNA levels of the DM gene.

Myotonic dystrophy (DM) results from the amplification of an unstable CTG repeat in the 3' untranslated region of a transcript encoding a putative serine/threonine kinase. We have analysed the amplification of the repeat and the steady state levels of the DM kinase (DMK) mRNA in tissues and cell lines from normal and congenital DM individuals. Southern blot analysis of DNA samples from a severely affected neonate shows somatic heterogeneity of the repeat in all tissues studied. RNA analyses on these tissues show a marked increase in DMK steady state mRNA levels. We demonstrate that the mutant DMK allele is expressed regardless of the number of CTG repeats and that the increase in DMK mRNA levels is due to elevated mutant mRNA levels. We postulate that elevated DMK levels explains the dominant inheritance pattern of DM.

Alleles↗
PubMed1997

Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing.

Several X-linked disorders affect females disproportionately or exclusively. These including focal dermal hypoplasia, oral-facial-digital syndrome type I (ref. 3) and epilepsy with bilateral periventricular heterotopias. X-linked dominant inheritance with male lethality is probably responsible for sex-limited expression of these disorders, as affected women have frequent spontaneous abortions and the sex ratio of their live offspring is often skewed. The same inheritance pattern has been proposed for Rett syndrome, Aicardi syndrome and microphthalmia with linear skin defects, but in these sporadic conditions, evidence of male lethality is lacking. We investigated an unusual family with epilepsy and mental retardation limited to females (EFMR, #121250 in ref. 9); this disorder is transmitted both by females and by completely unaffected carrier males. Assignment of the EFMR disease locus (EFMR) to the X chromosome indicates that selective involvement of females in X-linked disease may in some instances result from male sparing rather than male lethality.

Cerebral Cortex↗
PubMed2002

Segregation at three loci explains familial and population risk in Hirschsprung disease.

Hirschsprung disease (HSCR), the most common hereditary cause of intestinal obstruction, shows considerable variation and complex inheritance. Coding sequence mutations in RET, GDNF, EDNRB, EDN3 and SOX10 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). We conducted a genome scan in families with S-HSCR and identified susceptibility loci at 3p21, 10q11 and 19q12 that seem to be necessary and sufficient to explain recurrence risk and population incidence. The gene at 10q11 is probably RET, supporting its crucial role in all forms of HSCR; however, coding sequence mutations are present in only 40% of linked families, suggesting the importance of noncoding variation. Here we show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET. This study demonstrates by a complete genetic dissection why the inheritance pattern of S-HSCR is nonmendelian.

Alleles↗
PubMed2005

Normal huntingtin function: an alternative approach to Huntington's disease.

Several neurological diseases are characterized by the altered activity of one or a few ubiquitously expressed cell proteins, but it is not known how these normal proteins turn into harmful executors of selective neuronal cell death. We selected huntingtin in Huntington's disease to explore this question because the dominant inheritance pattern of the disease seems to exclude the possibility that the wild-type protein has a role in the natural history of this condition. However, even in this extreme case, there is considerable evidence that normal huntingtin is important for neuronal function and that the activity of some of its downstream effectors, such as brain-derived neurotrophic factor, is reduced in Huntington's disease.

Animals↗
PubMed2006

Enriched environments, experience-dependent plasticity and disorders of the nervous system.

Behavioural, cellular and molecular studies have revealed significant effects of enriched environments on rodents and other species, and provided new insights into mechanisms of experience-dependent plasticity, including adult neurogenesis and synaptic plasticity. The demonstration that the onset and progression of Huntington's disease in transgenic mice is delayed by environmental enrichment has emphasized the importance of understanding both genetic and environmental factors in nervous system disorders, including those with Mendelian inheritance patterns. A range of rodent models of other brain disorders, including Alzheimer's disease and Parkinson's disease, fragile X and Down syndrome, as well as various forms of brain injury, have now been compared under enriched and standard housing conditions. Here, we review these findings on the environmental modulators of pathogenesis and gene-environment interactions in CNS disorders, and discuss their therapeutic implications.

Animals↗
PubMed2000

Evidence of pleiotropic loci for fasting insulin, total fat mass, and abdominal visceral fat in a sedentary population: the HERITAGE family study.

OBJECTIVE: To examine whether there is a major gene effect on fasting insulin and pleiotropic loci for fasting insulin, total fat mass (FM), and abdominal visceral fat (AVF). RESEARCH METHODS AND PROCEDURES: A major gene hypothesis for fasting plasma insulin levels was assessed using segregation analyses of data on 495 members in 98 normolipidemic sedentary families of white descent who participated in the HERITAGE Family Study. RESULTS: Segregation analyses were performed on insulin adjusted for age, on insulin adjusted for age and FM, and on insulin adjusted for age and AVF. Before adjustment for AVF and FM, a major gene effect on fasting insulin levels was indicated. The putative locus accounted for 54% of the variance under a recessive inheritance pattern, affecting 11% of the sample (i.e., allele frequency = 0.33). However, after adjusting for the effects of AVF or FM, neither a major effect alone nor a multifactorial component alone could be rejected, and support for a major gene was equivocal, i.e., neither the hypothesis of Mendelian tau values or that of the equal tau(s) were rejected and the equal tau model fit the data better than the Mendelian tau model. This pattern (i.e., major gene evidence for insulin before but not after adjustment for AVF or FM) suggests that there is a putative locus with pleiotropic effects on both insulin and FM and another pleiotropic locus for both insulin and AVF. DISCUSSION: Although these data do not directly support an additional major gene for insulin independent of AVF and FM, such support cannot be ruled out because there is still a significant major effect on FM- or AVF-adjusted insulin (albeit the Mendelian nature of this effect is ambiguous).

Abdomen↗
PubMed2000

Inheritance of the waist-to-hip ratio in the National Heart, Lung, and Blood Institute Family Heart Study.

OBJECTIVE: Considering that waist-to-hip ratio (WHR) is a simple anthropometric measure of obesity and is a better predictor of coronary heart disease than body mass index (BMI), the genetic underpinnings of WHR are of interest. The inheritance pattern of WHR, before and after adjustment for BMI (WHR-BMI), was investigated in 2713 individuals from 1038 nuclear families in the National Heart, Lung, and Blood Institute Family Heart Study (NHLBI-FHS). RESEARCH METHODS AND PROCEDURES: Waist and hip measurements were taken twice, and the means of the measurements were used to calculate the WHR. Adjustments for age were carried out separately by sex, using stepwise multiple regression procedures for WHR and WHR-BMI phenotypes. Segregation analysis was applied using the unified model as implemented in the computer program POINTER. RESULTS: For age-adjusted WHR, the segregation results suggested an additive major gene that accounts for 35% of the phenotypic variance, and approximately 30% of the sample are homozygous for the "high" genotype. The results for age- and BMI-adjusted WHR were also compatible with a major gene; however, the multifactorial model provided the most parsimonious fit to the data. DISCUSSION: Although the genetic mechanisms for several obesity traits have been studied, tests of Mendelian segregation on this simple anthropometric measure (WHR) have not been reported previously. This study provides evidence for the presence of a major gene for age-adjusted WHR, suggesting that it is an appropriate trait for further genetic analysis, especially because it has strong predictive value and probably relates biologically to cardiovascular risk.

Body Constitution↗