[Genetic aspects of valvulopathies]. / Aspects Génétiques des Valvulopathies.

Valvular dystrophies due to myxoid degeneration are common and potentially serious cardiac pathologies. They constitute a heterogeneous group of which the most usual is idiopathic mitral valvular prolapse (Barlow's disease). The majority of mitral valvular prolapses are sporadic, but there are several familial forms. Transmission is usually autosomal dominant with incomplete penetrance and variable expression. The first chromosomal location to be identified was on the 16p11-13 chromosome. Since then, two other loci have been identified on the 11p15.4 and 13q31-32 chromosomes. Our team has recently identified the first gene responsible for myxoid valvulopathy linked to the X chromosome, from a large family of 318 members. This is the gene that codes for filamin A, which is a cytoskeleton protein. The frequency of mutations in this gene is still unknown, but out of 7 families in which transmission was compatible with X-linked transmission, mutations were discovered in 4 of the families. Thanks to a genetic epidemiological approach, we have also demonstrated that there are familial forms of aortic stenosis, which are probably common. Identification of the genes implicated in these common forms of valvular pathology is important, as it will allow a better understanding of the pathophysiology of these valvular disorders and could lead to better therapeutic management in the future.

Familial deafness, congenital heart defects, and posterior embryotoxon caused by cysteine substitution in the first epidermal-growth-factor-like domain of jagged 1.

In the present study, we report a kindred with hearing loss, congenital heart defects, and posterior embryotoxon, segregating as autosomal dominant traits. Six of seven available affected patients manifested mild-to-severe combined hearing loss, predominantly affecting middle frequencies. Two patients were diagnosed with vestibular pathology. All patients had congenital heart defects, including tetralogy of Fallot, ventricular septal defect, or isolated peripheral pulmonic stenosis. No individual in this family met diagnostic criteria for any previously described clinical syndrome. A candidate-gene approach was undertaken and culminated in the identification of a novel Jagged 1 (JAG1) missense mutation (C234Y) in the first cysteine of the first epidermal-growth-factor-like repeat domain of the protein. JAG1 is a cell-surface ligand in the Notch signaling pathway. Mutations in JAG1 have been identified in patients with Alagille syndrome. Our findings revealed a unique phenotype with highly penetrant deafness, posterior embryotoxon, and congenital heart defects but with variable expressivity in a large kindred, which demonstrates that mutation in JAG1 can cause hearing loss.

Selenium status in an iodine deficient population of the West Ivory Coast.

Selenium is an essential trace element which is part of the active site of seleno-dependent glutathione peroxidase and type 1 deiodinase. Therefore, it plays a key role in thyroid hormone metabolism. The present work was undertaken in order to evaluate selenium status in two Ivory Coast populations: the first with high (Glanlé) and the second with low (Abidjan) prevalence of iodine deficiency. Selenium, glutathione peroxidase, glutathione reductase, glutathione and diglutathione were determined in blood and/or urine. In plasma and erythrocytes, selenium and glutathione peroxidase were dramatically low in Glanlé. Compared to Abidjan, selenium, glutathione peroxidase, vitamin E and riboflavin status were decreased whereas diglutathione was increased in Glanlé. The results clearly demonstrate a selenium deficiency and suggest an oxidant stress in Glanlé. Causes and consequences of this selenium deficiency and oxidant stress remain to be determined.

A worldwide analysis of AG molecular diversity inferred from serology.

Ten population samples from different geographic origins were tested serologically for the AG polymorphism of human beta-lipoproteins. Their haplotype frequencies were used with previously published data to perform a wide analysis of AG genetic differentiations throughout the world. Coancestry coefficients were computed from weighted F(ST)s among populations by using a matrix of molecular distances among AG haplotypes, which is here determined on the basis of DNA studies. Coancestry coefficients derived from unweighted F(ST)s and more classical Prevosti distances were computed on the same data and used for a comparison. In all cases a highly significant correlation was found between genetics and geography on a worldwide scale, while the significance of the correlation with linguistics differed. A test of significance of the pairwise F(ST)s among populations also gave different results depending on whether the molecular distance matrix among AG haplotypes was included. Globally, this study shows that in spite of being highly significantly correlated to each other, different genetic distance measures can lead to different interpretations of the same data set. Moreover, the elucidation of the molecular models related to the presently known serological polymorphisms may represent an additional tool for analyzing such polymorphisms in human population genetics studies.

Neonatal screening for cystic fibrosis in Brittany, France: assessment of 10 years' experience and impact on prenatal diagnosis.

BACKGROUND: Neonatal screening for cystic fibrosis has been a subject of debate over the past few years. This study assesses 10 years of neonatal screening in Brittany, France, and examines its impact on prenatal screening of subsequent pregnancies in couples with an affected child. METHODS: The study included all the neonates screened for cystic fibrosis in Brittany from Jan 1, 1989, to Dec 31, 1998. The screening consisted of an immunoreactive trypsinogen assay from dried blood spots, plus, from 1993, mutation analysis. Data were collected on incidence of cystic fibrosis, and genotypic and biochemical characteristics. The use of prenatal screening of subsequent pregnancies in affected families was also investigated. FINDINGS: Of the 343,756 neonates screened, 118 children with cystic fibrosis were identified, giving an incidence of one in 2913. All mutated alleles were characterised: 34 different mutations resulting in 36 genotypes were detected. The introduction of DNA analysis into the protocol greatly reduced the recall rate and increased the sensitivity of the test. The mean cost of the screening programme was US$2.32 per screened child. 39 (34%) of the families identified by neonatal screening opted for subsequent prenatal diagnosis at least once. 12 couples would have benefited from this procedure while their first child was still symptom-free. 42 healthy children were born, and 18 pregnancies were terminated (therapeutic abortion rate of 100%). INTERPRETATION: We have shown the feasibility of neonatal screening for cystic fibrosis in Brittany. Through the detection of a large range of mutations, neonatal screening provides the opportunity for more reliable prenatal diagnosis and cascade screening. The neonatal screening programme described here could provide a good model for other countries intending to initiate such a scheme.

Microsatellite haplotypes associations with 5 CFTR mutations in "Grande Brière", an isolate located in southern Brittany.

The variability at three microsatellites in the Cystic Fibrosis Transmembrane Conductance Regulator Gene (CFTR) locus has been studied for frequent mutations encountered in an isolated population of "Grande Brière", a small region located in Southern Brittany. Fluorescent multiplex PCR of these microsatellites were assayed in 16 Cystic Fibrosis (CF) families carrying 5 different mutations. The four most frequent haplotypes on df508 chromosomes were the same as those found in Northern France and Europe but the distribution of these haplotypes provides new enlightenment on the population origin of this insular community.

Anthropogenetical analysis of abnormal human alpha-globin gene cluster arrangement on chromosome 16.

An earlier study of human globin gene polymorphism in two Adriatic islands of Olib and Silba showed an abnormal arrangement of alpha-globin genes in two different individuals. The next step was to determine the degree of the kinship relationship between the two probands, one with a deleted and another with triplicated alpha-globin gene on the island Silba, and to determine the stability of this disorder through generations. We reviewed the parish registers (Status Animarum) of the island of Silba, dating from the year 1527, and constructed family trees for the two probands. Restriction endonuclease mapping was performed to study the arrangement of the alpha-globin genes in the offspring of our probands. A total of 183 ancestors completed the two family trees. The kinship relationship between them was established in the 5th, 6th, and 7th generation. The analysis of alpha-globin genes in the offspring of our probands showed the triplicated alpha-globin genes in two persons. We also found alpha-globin gene triplication in other three relatives. We did not find any deleted alpha-globin genes. We determined the kinship relationship between the two probands, one with deleted and the other with triplicated alpha-globin genes. This finding enabled us to determine the stability of this gene disarrangement through generations. It also showed new possibilities in anthropogenetic research, by combining the analyses of parish registers with those of modern genetic methods, such as restriction endonuclease mapping.

The analysis of population structure based on morphometric dimensions of metacarpal bones (the Island of Krk, Croatia).

The aim of this study was to investigate: 1) a possibility of using the morphometric dimensions of metacarpal bones for approximation of biological distances, and 2) a relationship of biological matrices, based on the morphometric dimensions of metacarpal bones to other biological (dermatoglyphic, genetic), bio-cultural (migration) and geographic variables. The morphometry of the metacarpal bones was performed according to Barnett and Nordin procedure and biological distances were estimated using Mahalanobis D2 method. Population structure was assessed through Mantel's permutation test using E2 genetic distances for classical serogenetic markers, DA genetic distances for HLA, DSW genetic distances for STRs, geographic distances expressed in kilometres, and migration kinship matrix estimated according to the method proposed by Malécot and modified by Morton. This study clearly indicated the need for applying factorial analytical approach to study the factor structure of morphometric variables that may be measured on six metacarpal bones as well as the need for conducting complex family and segregation analyses to address not only the intriguing issue of genetic vs. ecological impact onto the bone mineral turnover, but also to test the hypothesis of major gene control in determining bone mineral density.

[Management strategies for endemic goiter in developing countries]. / Stratégies de prise en charge d'une endémie goitreuse en situation de développement.

Despite significant progress in the last decades, endemic goiter remains a serious public health problem in the developing world, especially in Africa. Even in countries that have successfully reduced overall incidence to acceptable levels, endemic areas often remain. This persistence is due to the inadequacy of preventive measures and poor follow-up of control programs. The main etiologic factor in endemic goiter is inadequate dietary intake of iodine. This commonly occurs in communities depending exclusively on local produce grown on iodine-poor land, especially in mountain areas. Endemic goiter is epidemiologically associated with cretinism, deaf-mutism, and mental retardation. Even mild iodine deficiency leads to clinical hypothyroidism and moderate myxoedema with significantly reduced intellectual performance. Prevention of endemic goiter depends mainly on increasing the iodine intake of people in endemic areas. When iodine intake reaches the estimated adult minimum requirement (100 to 150 micrograms per day), the prevalence of goiter decreases. Two approaches have been used to increase iodine intake. The first consists of adding iodine to food staples such as table salt. The second consists of medical treatment using agents such as iodized oil. Iodization or iodination of salt is the most widespread and cost-effective method of prevention. Administration of iodized oil has been used only in severely endemic areas and in regions where reliable provision of iodinized salt is prevented by geographical barriers or political factors. However, iodized oil has been helpful in the start-up phase of prevention programs using iodized salt, either as an emergency measure or as a mean of convincing officials of the efficacy of iodine prophylaxis.

Founder effect in GLC1A-linked familial open-angle glaucoma in Northern France.

Open-angle glaucoma (POAG) is a highly prevalent cause of visual impairment. Six families grouping 71 living patients affected with juvenile-onset and middle-age POAG (age at diagnosis ranging from 10 to 65 years) were linked to the GLC1A locus. All patients carried a mutation of an evolutionarily conserved asparagine residue to a lysine at position 480 (N480K) in the olfactomedin-homology domain, which is encoded by the third exon of the GLC1A gene. The N480K mutation was also identified in 14 unaffected carriers who are at high risk of developing POAG. Although four of the families had ancestors identified in Northern France, the pedigrees could not be interconnected by genealogical investigation. However, haplotype analysis indicated that all the carriers had inherited the N480K mutation from the same founder. Screening of a selected set of 67 POAG patients who originated from Northern France and underwent trabeculectomy before the age of 50, detected one patient with the N480K mutation associated with the same disease haplotype already characterized in the 6 families. This group of 72 POAG patients is the largest one having a GLC1A mutation in common and provides a unique tool to investigate the factors influencing the variable expressivity of the GLC1A gene.

Genetic factors in iodine deficiency disorders: a general review.

This review presents a summary of what is known about genetic factors possibly involved in iodine deficiency disorders. After an overview on thyroid iodine metabolism and the role of environmental factors in endemic goitre, we analyse genetic studies on endemic goitre reported in the literature. We hypothesize that endemic goitre is a multifactorial disease in which the major factor would be of environmental nature (iodine deficiency) with a lesser role for genetic factors. Mutations, in a heterozygote state, of one of the genes involved in tiered hormonogenesis could lead to a less effective metabolic pathway in the iodine transport or hormonogenesis. We also briefly review various hereditary disorders which may be involved in endemic goitre. Then, we postulate that the presence of some genetic variants in the population or the heterozygote status of individuals for thyroid hereditary disorders may influence the degree of the thyroid enlargement and/or hypothyroidism.

Endemic goitre: a research protocol elaboration for eradication.

The iodine deficiency (ID), which affects 1 person out of 6, is relatively neglected by the responsible of Public Health Service, particularly in developing countries. Consequences of ID are far from being negligible: mental retardation, hypofertility, hyperplasia, carcinoma, early ageing and, in very exposed areas, endemic cretinism. Nevertheless, eradication is easy and cheap but it requires rigorous protocols and control of results. The elaboration of these protocols is complex because it must be adapted to environment, population and financial possibilities of concerned countries. Based on our experience in this field, we propose a combined protocol, between the Public Health too liberal approach and that of too expensive research, which can be adapted to several situations.

Endemic cretinism in a traditional society in Mali: from the collectivity to the individual.

The prevalence of endemic cretinism was measured in a village belonging to the Bwa ethnic group in Mali liable to iodine deficiency and suffering from endemic goitre. In this village according to mental and motor handicaps found in cretinism, we used two psychometric tests: the Raven's Progressive Matrice (PM 47) and a "peg test". Using the fiduciary inference method on the two tests associated with a clinical and qualitative approach, we obtained a prevalence of myxedematous cretinism close to 1.2%.

The prevalence of goitre and cretinism in a population of the west Ivory Coast.

Iodine deficiency is a major public health problem in developing countries. The main areas where goitre is prevalent have been identified, but the different degrees of severity and the populations affected have not. Most countries are now attempting to obtain reliable and more extensive data. A pilot study was carried out in the Ivory Coast in order to improve epidemiological knowledge of iodine deficiency and collect the information required to set up an elimination programme. The aim of this study was to assess the prevalence of goitre and cretinism and to measure the main biochemical indicators of thyroid function (T3, T4 and TSH). The study involved 1433 people identified from a census. The prevalence of goitre was 50.3%. There was a significant difference between the examined ethnic groups: 52.7% of the Yacouba and 28.6% of the non-Yacouba had goitre. The most affected age group was 15-45 year. The predominance of women demonstrated the susceptibility of women at child-bearing age to develop the condition. The prevalence of cretinism was approximately 1.5%. Through the assessment carried out using a grid of clinical indicators, it was possible to identify 10 cases of laboratory proven myxedematous cretinism due to hypothyroidism. The concentration of iodine in foodstuffs was below the limit of detection (< 7.5 micrograms/kg) and iodine could not be detected in the water (< 1 microgram.l) The biological profile of the population was affected to a very limited extent, with a mean value (+/- standard deviation) for TSH of 1.93 (+/- 1.56) mIU/l (0.1-4.0) and a free T4 value of 10 (+/- 3.46) pmol/l (8.2-20). These initial results confirm the high prevalence of endemic goitre and the low iodine content of the soil, water and food in the investigated region. The study will be complemented by a nutritional investigation to improve the understanding of iodine balance, after which an appropriate action plan will be proposed.

Epidemiology and prophylaxis of endemic goitre in the Bwa village of Sirao (Mali).

A study was conducted in Mali, in some villages exposed to iodine deficiency disorders (IDD). To treat and, above all, prevent endemic goitre, Lipiodol UF was dispensed in two ways: by intra-muscular injection (475 mg I) or by oral administration (48 mg I to 240 mg I). In two cases, hormone levels regained normal values and thyroid hypertrophies regressed significantly. Nevertheless, the impact of the treatment on the size of the goitres seems to be in favour of injections; which is probably due to the fact that in the village which received Lipiodol UF per os, many goitres were nodular.

Registers and follow-up methods of populations in a public health survey: the example of the village Glanlé in Ivory Coast.

Demography has a fundamental place in a public health survey, and it is essential to provide the population follow-up. A population exhaustive census is the first compulsory phase. It turns out that this phase is necessary if we want to know with precision the size of the population studied and its main demographic characteristics (sex, age ...). The census allows us to provide a real population follow-up, in order to measure the evolution of the different disorders and to estimate the effects of a prophylaxis on each individual in a precise time. This follow-up requires a computerized population register which contains all the information concerning every individual. This data file is updated with new data collected by next surveys. The realization of the nominal population pyramid, is a complementary tool to the population follow-up. Each individual, characterized by sex and age, is allocated a position in the pyramid by his identification number. The figurative contrasts show several cases noticed according to the studied events. The reconstruction of the genealogy represents another form of the population follow-up, by reconstructing biological kinship relationships between the inhabitants.

Application of HLA class II polymorphism analysis to the study of the population structure of the Island of Krk, Croatia.

The population structure of the northern Adriatic island of Krk, Croatia, was studied using PCR methodology and nonradioactive oligonucleotide hybridization for the analysis of HLA-DRB1, DRB3, DRB4, DRB5, DQA1, and DQB1 polymorphisms. Allele frequencies, genetic kinship (R), and genetic distances (E2) were computed, and correlations between distance (genetic, linguistic, geographic) and kinship (migration) matrices were examined. The results, reflecting past (micro-) evolutionary processes, indicate that ethnohistorical and sociocultural events rather than geographic distances are the primary determinants of today's population structure of the island.

Recurrent mutations in a single exon encoding the evolutionarily conserved olfactomedin-homology domain of TIGR in familial open-angle glaucoma.

Primary open-angle glaucoma (POAG) is a highly prevalent cause of irreversible blindness which associates cupping of the optic disc and alteration of the visual field, elevation of intraocular pressure being a major risk factor. Provided diagnosis is made at an early stage, treatments are available to prevent visual impairment. A locus, GLC1A, has been mapped on chromosome 1q23-q25 in several families affected with juvenile-onset POAG (JOAG) and also in some families affected with juvenile and middle-age onset POAG. Recently, three mutations of the TIGR (Trabecular meshwork-Induced Glucocorticoid Response) gene were shown to be responsible for the disease in several American families and in unrelated POAG patients. We now describe five new mutations in eight French families. All mutations known to date appear to concentrate in the evolutionarily conserved C-terminal domain of TIGR which bears homology to frog olfactomedin, an extracellular matrix glycoprotein of the olfactory epithelium, to rat and human neuronal olfactomedin-related proteins and to F11C3.2, a protein from Caenorhabditis elegans . Moreover, this conserved domain of TIGR is encoded by a single exon to which mutation screening could be limited. Surprisingly, the TIGR message, which is abundantly transcribed in the trabecular meshwork and also in the ciliary body and the sclera, is not expressed in the optic nerve whose degeneration is, however, the primary lesion of POAG.