Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke

Haemorrhagic stroke accounts for approximately 20% of stroke cases and porencephaly is a clinical consequence of perinatal cerebral haemorrhaging. Here we report the identification of a novel dominant G702D mutation in the collagen domain of COL4A2 (collagen IV alpha chain 2) in a family displaying porencephaly with reduced penetrance. COL4A2 is the obligatory protein partner of COL4A1 but in contrast to most COL4A1 mutations, the COL4A2 mutation does not lead to eye or kidney disease. Analysis of dermal biopsies from patient and his unaffected father, who also carries the mutation, revealed that both display basement membrane (BM) defects. Intriguingly, defective collagen IV incorporation into the dermal BM was only observed in the patient and was associated with endoplasmic reticulum (ER) retention of COL4A2 in primary dermal fibroblasts. This intracellular accumulation led to ER-stress, unfolded protein response activation, reduced cell proliferation and increased apoptosis. Interestingly, absence of ER retention of COL4A2 and ER-stress in cells from the unaffected father indicate that accumulation and/or clearance of mutant COL4A2 from the ER may be a critical modifier for disease development. Our analysis also revealed that mutant collagen IV is degraded via the proteasome. Importantly, treatment of patient cells with a chemical chaperone decreased intracellular COL4A2, ER-stress and apoptosis, demonstrating that reducing intracellular collagen accumulation can ameliorate the cellular phenotype of COL4A2 mutations. Importantly, these data highlight that manipulation of chaperone levels, intracellular collagen accumulation and ER-stress are potential therapeutic options for collagen IV diseases including haemorrhagic stroke

Three new PAX6 mutations including one causing an unusual ophthalmic phenotype associated with neurodevelopmental abnormalities

The PAX6 gene was first described as a candidate for human aniridia. However, PAX6 expression is not restricted to the eye and it appears to be crucial for brain development. We studied PAX6 mutations in a large spectrum of patients who presented with aniridia phenotypes, Peters' anomaly, and anterior segment malformations associated or not with neurological anomalies.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Éléments de génétique humaine et leurs implications en psychologie

PSYEDU2, GENE007info:eu-repo/semantics/published

La déficience auditive et le conseil génétique.

Journal ArticleReviewinfo:eu-repo/semantics/publishe

Éléments de génétique humaine et leurs implications en psychologie

2e édition 2001-02/1Vente uniquement aux étudiants suivant le cours susmentionné, sur présentation de leur carte d'étudiant, PSYEDU2, GENE007info:eu-repo/semantics/published

Rôle du conseil génétique dans la décision de procréation.

In the literature dealing with the impact of genetic counsel in the reproduction decision, two aspects are discussed: 1. memorization and appraisal of the recurrence risk, chosen options for family planning, appraisal of genetic counsel by the patients 2. mechanisms of decision making and psychological impact of genetic counsel.English AbstractJournal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Le conseil génétique: bilan de 1000 dossiers.

1000 cases of genetic counseling have been reviewed. Most patients are sent to the genetic center by gynecologists (68.4%), mostly because of a personal or previous familial history (64%). This previous history concerns mainly congenital malformations (44%, 283/640) and mental retardation (24%, 154/640). Generally, the patients consult outside a pregnancy, nevertheless one fourth comes after conception and this occurs more often when the proband is a family member (38% versus 19% when the proband is a spouse and 20% when the proband is a child). Ten percent of the patients knowing they could be at risk because spouse or child is affected consult after having already had a child or having had another child. The mode of inheritance of the diseases for which patients with previous family history consult is as follows: mendelian inheritance (36%), multifactorial inheritance (19%), chromosomal defect (18%), non genetic (5%), variable inheritance (2%), unknown (15%) and insufficient information (5%). The majority of patients coming for previous familial history could be tranquilized, the recurrence risk was either small or minimal. In 2.6% of the cases, a high recurrence risk has been given and the risk could not be evaluated in 7% of the cases. The importance of genetic counseling is stressed by the fact that antenatal diagnosis could be proposed to half of the patients with a recurrence risk equal or higher than 1%.English AbstractJournal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

The importance of determining the mode of inheritance for the estimation of recurrence risks.

Recurrence risks for the generalised single locus model and for the multifactorial model have been derived and compared. First the areas of overlap for the two models were determined and sets of parameters chosen to represent these overlap areas. Certain sets of parameters for the single locus model give recurrence risks in sibships similar to these for multifactorial inheritance. Other sets (representing very low penetrant dominant genes) give markedly lower risks. Similar results hold for more complex family histories. Empiric risks for families with two or more affected individuals are needed so as to indicate the trend of the increase in risk which could then be extrapolated to other families and be used in genetic counseling.Journal Articleinfo:eu-repo/semantics/publishe

Le conseil genetique aux diabetiques

Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Familial occurrence of Summitt syndrome or a variant example of Carpenter syndrome?

In this report, we describe three sibs presenting an identical malformation syndrome i.e. acrocephaly, brachydactyly, prominent metopic ridge, broad depressed nasal bridge, narrow maxillae, obesity and normal intelligence. We discuss the relationship between this combination of clinical signs and symptoms most compatible with the diagnosis of Summitt syndrome and the Carpenter syndrome.Case ReportsJournal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe