A Single Mutation of the Fumarylacetoacetate Hydrolase Gene in French Canadians with Hereditary Tyrosinemia Type I

Grompe, Markus; St.-Louis, Maryse; Demers, Sylvie I.; Al‐Dhalimy, Muhsen; Leclerc, B.; Tanguay, Robert M.

doi:10.1056/nejm199408113310603

Cited by 122 publications

(71 citation statements)

References 16 publications

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“…This primary investigation was carried out in 485 adolescents recruited from a French Canadian population with a known founder effect in which fewer gene variants are expected to contribute to the determination of complex traits, such as BP and autonomic function. [15][16][17] In addition, a replication study was carried out in an independent sample of 298 adults originating from 69 hypertensive families who were recruited from the same French Canadian founder population. 18 …”

Section: Clinical Perspective On P 269mentioning

confidence: 99%

“…[15][16][17] It originates from ancestors of French descent who migrated to this region in the early 19th century. The population has experienced high intrinsic growth, from 5200 inhabitants in 1852 to 285 000 at present.…”

Section: French Canadian Founder Populationmentioning

confidence: 99%

“…Because of the founder effect, the prevalence of several recessive disorders is higher in the Saguenay-Lac St. Jean region than in other populations, 15 and limited allelic diversity exists among patients with these disorders. 16,17 Written consent of the parents and assent of the adolescents (adolescent sample) and subjects (adult sample) were obtained before the commencement of data collection. The Research Ethics Committee of the Chicoutimi Hospital approved the study protocols.…”

Section: French Canadian Founder Populationmentioning

confidence: 99%

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A Common Variant of the FTO Gene Is Associated With Not Only Increased Adiposity but Also Elevated Blood Pressure in French Canadians

Pausová

Syme

Abrahamowicz

et al. 2009

Circ Cardiovasc Genet

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Background-FTO is the first gene established as contributing to common forms of obesity. The gene is highly expressed in the hypothalamus and is thought to mediate this effect through its influence on energy homeostasis. The hypothalamus, however, also regulates blood pressure (BP). Therefore, we investigated whether the FTO-risk variant is associated not only with increased adiposity but also with elevated BP and whether the latter may be mediated, in part, by increased sympathetic modulation of vasomotor tone. Methods and Results-The primary study was carried out in 485 adolescents recruited from a French Canadian founder population who underwent detailed body-composition and cardiovascular phenotyping. Body fat was examined with MRI, bioimpedance, and anthropometry. BP was recorded beat to beat at rest and during physical and mental challenges. Sympathetic modulation of vasomotor tone was assessed with power spectral analysis of BP. We found that individuals with the FTO-risk genotype compared with those without it demonstrate greater adiposity, including the amount of intra-abdominal fat (by 38%). They also showed higher systolic BP throughout the entire protocol, with a maximum difference during a mental stress (6.4 [1.5 to 11.3] mm Hg). The difference in BP was accompanied by elevated index of sympathetic modulation of vasomotor tone. A replication in an independent sample of adults from the same founder population confirmed the association between FTO and BP. Conclusions-These results suggest that, in a French Canadian founder population, FTO may increase not only risk for obesity, as demonstrated in other populations, but also for hypertension. The latter may be related, at least in part, to the regulation of sympathetic vasomotor tone. (Circ Cardiovasc Genet. 2009;2:260-269.)

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Section: Clinical Perspective On P 269mentioning

confidence: 99%

Section: French Canadian Founder Populationmentioning

confidence: 99%

Section: French Canadian Founder Populationmentioning

confidence: 99%

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A Common Variant of the FTO Gene Is Associated With Not Only Increased Adiposity but Also Elevated Blood Pressure in French Canadians

Pausová

Syme

Abrahamowicz

et al. 2009

Circ Cardiovasc Genet

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“…15 Because of the founder effect, the prevalence of several recessive disorders is higher in the SLSJ than in other populations, 16 and limited allelic diversity exists among patients with these disorders. 17,18 The families were selected on the basis of having Ն2 siblings with hypertension (onset at Յ55 years of age) and dyslipidemia. Hypertension was defined as having diastolic BP Ն90 mm Hg on 2 occasions or currently taking antihypertensive medication, with hypertension being documented in medical records.…”

Section: Subjectsmentioning

confidence: 99%

Genome-Wide Scan for Linkage to Obesity-Associated Hypertension in French Canadians

et al. 2005

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Abstract-Essential hypertension is a heterogeneous disorder that is thought to develop because of several overlapping subsets of underlying mechanisms. One such causal pathway may involve pathophysiological alterations induced by obesity. In the present study, we examined whether investigating clinically defined subtypes of hypertension, such as obesity-associated hypertension, facilitates the search for its genes. Fifty-five extended families were selected on the basis of having Ն2 siblings affected by hypertension from a geographically remote French-Canadian population. Fifteen of these families showed a high prevalence (Ն70%) of obesity. Genome-wide scan using qualitative multipoint linkage analysis (GeneHunter 2.1; marker density Ͻ10 cM) was performed in the entire set of hypertensive families and the subset with high prevalence of obesity. In the scan involving all 55 families, the most significant loci (logarithm of odds [LOD] scoreϭ2.5) were identified on chromosomes 1 (D1S1597) and 11 (D11S1999). In the scan including only the subset of families with obesity-hypertension, the most significant locus (LOD scoreϭ3.1) was found on chromosome 1 in the same region as the scan involving all families (D1S1597). Genotyping additional markers increased the significance of this locus (LOD scoreϭ3.5) and refined its position (D1S2672). Several candidate genes of obesity-hypertension are located in close proximity; these include the tumor necrosis factor receptor 2 and atrial natriuretic peptide genes. These results suggest that investigating clinically defined subtypes of hypertension, such as obesity-associated hypertension, may facilitate the search for genes of this complex disorder. Key Words: hypertension, obesity Ⅲ genetics E ssential hypertension is a heterogeneous disorder that develops because of several overlapping subsets of pathophysiological mechanisms. Obesity is a leading risk factor for the disorder, and as such, may be a key element in one of these subsets. Prospective cohort investigations have demonstrated positive correlations between weight gain and blood pressure (BP) elevation. 1 For example, in the Framingham Study, it was estimated that for each 4.5 kg of weight gain, there is an associated increase in systolic BP of 4 mm Hg in both men and women. 2 Pathophysiological mechanisms linking the increases in adiposity to the elevations in BP are not very well understood. They may include alterations in renal handling of sodium and water, sympathetic nervous system activity, insulin sensitivity, and fatty acid metabolism, 3 with some of these alterations being induced by hormones, growth factors, and cytokines expressed by adipose tissue in response to its expansion.Hypertension and obesity are multifactorial traits determined by a complex interplay of genes and environments. 4 A number of genes contribute to the determination of each of these traits, and their actions are simple, additive, or more complex, characterized by phenomena such as epistasis and pleiotropy. Furthermore, hypertension and ...

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“…This mutation is common among patients of French Canadian origin and was also reported in 45% of the West European patients (Grompe et al, 1994, Ploos van Amstel et al, 1996. The observation of this mutation in patient 3 whose family has resided in the same village for the past 500 years, suggests that the mutation has either occurred multiple times world wide or has originated in the Middle East.…”

Section: Resultsmentioning

confidence: 78%

Mutation analysis of the FAH gene in Israeli patients with tyrosinemia type I

et al. 2001

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Thirteen Israeli patients with type I tyrosinemia were studied. To the best of our knowledge, this group represents all of the patients that were diagnosed in Israel during the years 1987-1997. Their age of onset was variable but all the patients suffered from liver disease at presentation. Six died at 3 to 36 months of age, whereas the remaining 7, in whom NTBC was started at 5 to 30 months, are alive and well at 4 to 11 years. Three mutations were identified: a mis-splicing IVS8-1G>C mutation in a large Moslem kindred, Pro261Leu mutation in all Jewish patients, and the IVS12+5G>A mutation, commonly found in French Canadian patients.

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A Single Mutation of the Fumarylacetoacetate Hydrolase Gene in French Canadians with Hereditary Tyrosinemia Type I

Abstract: This study identified the most prevalent mutation causing hereditary tyrosinemia in French Canada; it also showed the feasibility of DNA-based testing for carriers in the population at risk.

Cited by 122 publications

References 16 publications

A Common Variant of the FTO Gene Is Associated With Not Only Increased Adiposity but Also Elevated Blood Pressure in French Canadians

A Common Variant of the FTO Gene Is Associated With Not Only Increased Adiposity but Also Elevated Blood Pressure in French Canadians

Genome-Wide Scan for Linkage to Obesity-Associated Hypertension in French Canadians

Mutation analysis of the FAH gene in Israeli patients with tyrosinemia type I

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