Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients

Lesca, Gaëtan; Génin, Emmanuelle; Blachier, Claire; Olivieri, Carla; Coulet, Florence; Brunet, Guy; Dupuis‐Girod, Sophie; Buscarini, Elisabetta; Soubrier, Florent; Calender, Alain; Danesino, Cesare; Giraud, Sophie; Plauchu, Henri

doi:10.1038/ejhg.2008.3

Cited by 36 publications

(34 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This analysis also revealed that there were no significant differences between the estimates based on a mutation rate of 0.0001 (N = 14 generations, range 7–24, CI = 95%), as suggested by Lesca et al [35], or a mutation rate of 0.00232 (N = 11 generations, range 6–21, CI = 95%), as suggested by Nothnagel et al [36]. There was also no significant difference in the result when employing the stepwise or equal methods of mutation (data not shown).…”

Section: Resultssupporting

confidence: 74%

Fabry disease: Evidence for a regional founder effect of the GLA gene mutation 30delG in Brazilian patients

Alencar

Netto

Ashton‐Prolla

et al. 2014

Molecular Genetics and Metabolism Reports

View full text Add to dashboard Cite

The Fabry disease is caused by mutations in the gene (GLA) that encodes the enzyme α-galactosidase A (α-Gal A). More than 500 pathologic variants of GLA have already been described, most of them are family-specific. In southern Brazil, a frequent single-base deletion (GLA 30delG) was identified among four families that do not recognize any common ancestral. In order to investigate the history of this mutation (investigate the founder effect, estimate the mutation age and the most likely source), six gene-flanking microsatellite markers of the X chromosome on the mutation carriers and their parents, 150 individuals from the same population and 300 individuals that compose the Brazilian parental populations (Europeans, Africans and Native Americans) were genotyped. A common haplotype to the four families was identified and characterized as founder. The age was estimated with two statistics software (DMLE 2.2 and ESTIAGE) that agreed with 11 to 12 generations old. This result indicates that the mutation GLA 30delG was originated from a single event on the X chromosome of a European immigrant, during the southern Brazil colonization between 1710 and 1740.

show abstract

Section: Resultssupporting

confidence: 74%

Fabry disease: Evidence for a regional founder effect of the GLA gene mutation 30delG in Brazilian patients

Alencar

Netto

Ashton‐Prolla

et al. 2014

Molecular Genetics and Metabolism Reports

View full text Add to dashboard Cite

show abstract

“…131 In keeping with the longevity of patients bearing heterozygous disease-causing mutations, haplotype analyses of ACVRL1 mutations suggest recurrent mutational events occurred 100 to 550 years ago. 8 While founder effects were also demonstrated, particularly for the ACVRL1 c.1112dupG mutation proposed to originate in a single inhabitant of the Haut-Jura mountains, again the original 21 mutation is estimated to have occurred more than 300 years ago. 8 However, worldwide, neither ENG nor ACVRL1 displays a common mutation with the number of reports of each mutation corresponding to first order decay kinetics 132 , and mutations occur throughout the genomic sequences.…”

Section: 2a) Geneticsmentioning

confidence: 99%

“…8 While founder effects were also demonstrated, particularly for the ACVRL1 c.1112dupG mutation proposed to originate in a single inhabitant of the Haut-Jura mountains, again the original 21 mutation is estimated to have occurred more than 300 years ago. 8 However, worldwide, neither ENG nor ACVRL1 displays a common mutation with the number of reports of each mutation corresponding to first order decay kinetics 132 , and mutations occur throughout the genomic sequences. 21 3 The situation may be somewhat different for SMAD4, when 25% of mutations appear to arise de novo.…”

Section: 2a) Geneticsmentioning

confidence: 99%

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

2010

View full text Add to dashboard Cite

Hereditary haemorrhagic telangiectasia, inherited as an autosomal dominant trait, affects approximately 1 in 5,000 people. The abnormal vascular structures in HHT result from mutations in genes (most commonly endoglin or ACVRL1) whose protein products influence TGF-ß superfamily signalling in vascular endothelial cells. The cellular mechanisms underlying the generation of HHT telangiectasia and arteriovenous malformations are being unravelled, with recent data focussing on a defective response to angiogenic stimuli in particular settings. For affected individuals, there is often substantial morbidity due to sustained and repeated haemorrhages from telangiectasia in the nose and gut. Particular haematological clinical challenges include the management of severe iron deficiency anaemia; handling the intricate balance of antiplatelet or anticoagulants for HHT patients in whom there are often compelling clinical reasons to use such agents; and evaluation of apparently attractive experimental therapies promoted in high profile publications when guidelines and reviews are quickly superseded. There is also a need for sound screening programmes for silent arteriovenous malformations. These occur commonly in the pulmonary, cerebral, and hepatic circulations, may haemorrhage, but predominantly result in more complex pathophysiology due to consequences of defective endothelium, or shunts that bypass specific capillary beds. This review will focus on the new evidence and concepts in this complex and fascinating condition, placing these in context for both clinicians and scientists, with a particular emphasis on haematological settings. Blood Reviews _ HHT 2010_ Shovlin 3 Overview of HHTHHT, also known as Osler Weber Rendu syndrome [1][2][3] , is one of the most common disorders to be inherited as an autosomal dominant trait. Careful epidemiological studies reveal that it affects approximately 1 in 5,000 individuals, 4,5 with regional differences, 6 and isolated communities displaying higher prevalences due to founder effects. 7 8 HHT was first described as a familial disease characterised by severe recurrent nasal and gastrointestinal bleeding with associated anaemia, and visible dilated blood vessels (telangiectasia) on the lips and finger tips. The majority of HHT patients are also affected by larger arteriovenous malformations (AVMs) in the pulmonary, hepatic, cerebral, pancreatic, spinal and other circulations. 1,2,9 These features, presented in more detail within Table 1, are used as criteria to diagnose HHT. 2 The spectrum of disease within the HHT umbrella has extended beyond the telangiectatic/AVM HHT pathology delineated by the Curaçao criteria. 2 More recently recognised features include pulmonary arterial hypertension 10 ; juvenile polyposis 11 ; pulmonary hypertension in the context of high output cardiac failure secondary to hepatic AVMs, when PH may be reversible after hepatic AVM treatment [12][13][14][15][16] ; a prothrombotic state associated with elevated plasma levels of factor VIII 17 , and poten...

show abstract

“…This mutation is frequent in patients of French descent and has been shown to be the result of a regional founder effect. 19 Four other ACVRL1 missense mutations were also selected because they were found in patients with conflicting results with respect to their molecular diagnosis: 3 ACVRL1 mutations (L381P, A482V, and R454W) corresponded to patients who also had a mutation in the ENG gene, whereas the last (R386C) was observed in a patient with 2 mutations located on the same ACVRL1 allele.…”

Section: Dna Constructsmentioning

confidence: 99%

Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations

Ricard

Bidart

Mallet

et al. 2010

Blood

Self Cite

View full text Add to dashboard Cite

Hereditary hemorrhagic telangiectasia (HHT)is an autosomal dominant genetically inheritable vascular dysplasia caused by mutations in genes encoding receptors of the transforming growth factor-␤ (TGF-␤) family: ENG, encoding endoglin (HHT1), and ACVRL1, encoding activin receptor-like kinase-1 (ALK1; HHT2). Our recent discovery of bone morphogenetic protein 9 (BMP9) as the specific ligand for ALK1 allowed us to reevaluate the functional significance of ACVRL1 mutations. We generated 19 ALK1 mutants reproducing HHT2 mutations (4 were novel mutations) found throughout the protein. We show that all ALK1 mutant proteins were expressed by transfected cells; most of them were present at the cell surface and retained their ability to bind BMP9 (except for the extracellular mutants). However, most were defective in BMP9 signaling. None of the ALK1 mutants had a dominant negative effect on wild-type ALK1 activity. These data demonstrate that mutations of ACVRL1 fit with a functional haploinsufficiency model affecting BMP9 signaling. Our study also identified 4 ACVRL1 mutations (D179A, R386C, R454W, and A482V) that did not alter the BMP9 responses that are polymorphisms and 2 novel mutations that are pathogenic (L381P and I485F). This demonstrates that the analysis of BMP9 responses can be used as a diagnostic tool by geneticists confronted with novel or conflicting ACVRL1 mutations. (Blood. 2010; 116(9):1604-1612)

show abstract

Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients

Cited by 36 publications

References 21 publications

Fabry disease: Evidence for a regional founder effect of the GLA gene mutation 30delG in Brazilian patients

Fabry disease: Evidence for a regional founder effect of the GLA gene mutation 30delG in Brazilian patients

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations

Contact Info

Product

Resources

About