SCAN domain-containing 2 gene (SCAND2) is a novel nuclear protein derived from the zinc finger family by exon shuffling. Gene 289:1–6

Abstract The SCAN domain is a recently recognized protein domain that characterizes a subfamily of the Krüppel-like zinc finger proteins. We have previously described a novel SCAN domain-containing 2 gene (SCAND2) that does not belong to the zinc finger family. We report structural and sequence analyzes of all known members of the SCAN family and use these data to illustrate a model of gene family evolution. Most of the SCAN containing genes share common gene organization features that support the proposed origin for SCAND2 by disruption of an ancestral SCAN-zinc finger gene by a retroposition event and subsequent exon shuffling.

The Dct−/− Mouse Model to Unravel Retinogenesis Misregulation in Patients with Albinism

We have recently identified encoding dopachrome tautomerase (DCT) as the eighth gene for oculocutaneous albinism (OCA). Patients with loss of function of suffer from eye hypopigmentation and retinal dystrophy. Here we investigate the eye phenotype in mice. We show that their retinal pigmented epithelium (RPE) is severely hypopigmented from early stages, contrasting with the darker melanocytic tissues. Multimodal imaging reveals specific RPE cellular defects. Melanosomes are fewer with correct subcellular localization but disrupted melanization. RPE cell size is globally increased and heterogeneous. P-cadherin labeling of newborn RPE reveals a defect in adherens junctions similar to what has been described in tyrosinase-deficient embryos. The first intermediate of melanin biosynthesis, dihydroxyphenylalanine (L-Dopa), which is thought to control retinogenesis, is detected in substantial yet significantly reduced amounts in postnatal mouse eyecups. L-Dopa synthesis in the RPE alone remains to be evaluated during the critical period of retinogenesis. The mouse should prove useful in understanding the molecular regulation of retinal development and aging of the hypopigmented eye. This may guide therapeutic strategies to prevent vision deficits in patients with albinism.Approches de génétique moléculaire et fonctionnelle pour déchiffrer les mécanismes physiopathologiques de l'albinisme oculocutané

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Anomalies du développement embryonnaire (apport au diagnostic du syndrome de Rubinstein-Taybi et recherche d'un gène impliqué dans une nouvelle forme de chrondrodrysplasie liée à l'X)

BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Mise en oeuvre de la technique d'hybridation génomique comparative sur puces à ADN pour l'analyse du dosage génique en génétique médicale

BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Analyse de réarrangements génomiques chez des patients atteints d'anomalies du développement embryonnaire (retard mental et malformations multiples congénitales; spectre oculo-auriculo-vertébral)

Notre travail s est intéressé aux anomalies du développement embryonnaire d origine génétique en étudiant : -d une part des patients associant des malformations congénitales multiples plus ou moins associées à un retard mental et à un syndrome dysmorphique, -et d autre part des patients présentant un phénotype particulier : le spectre oculo-auriculo-vertébral (OAVS) incluant le syndrome de Goldenhar. L analyse a consisté en l étude pangénomique de ces patients au moyen de puces à ADN (CGH-array), dans le but d identifier de nouveaux remaniements chromosomiques avec anomalie du nombre de copies. Nous avons identifié différentes régions variantes et analysé pour chacune leur caractère pathogène potentiel en fonction de leur nature, de leur taille, de leur caractère hérité ou de novo, de leur contenu en gènes et en polymorphismes du nombre de copies, des éléments déjà décrits dans les bases de données et la littérature. Les régions variantes identifiées ont été vérifiées par d autres techniques de recherche d anomalies de dosage génique. L ensemble de ces résultats permet de formuler des hypothèses quant à de nouveaux gènes candidats pour plusieurs symptômes observés, et pour l OAVS. Ils permettent d ajouter de nouvelles données à l ensemble des anomalies décrites depuis quelques années grâce à ces techniques innovantes.Our work focused on embryonic development abnormalities of genetic origin by studying: - patients with multiple congenital malformations associated or not associated with mental retardation and a dysmorphic syndrome; - patients presenting with the oculo-auriculo-vertebral spectrum (OAVS) that includes the Goldenhar syndrome. Patients were analysed by array-CGH in order to identifying novel chromosomal rearrangements with copy number abnormalities. We have identified several chromosomal regions with copy number variations and analysed for each of those their pathogenic potential, according to their nature, size, either inherited or de novo status, genes and copy number polymorphisms content, and data already reported both in databases and in the literature. The existence of a copy number variation was confirmed by other experimental approaches able to detect gene dosage abnormalities. Our results allowed discussing the possible involvement of candidate genes with respect to the symptoms observed in the patients and to OAVS. They also allowed to add new data to the growing field of copy number variations gathered over the recent years.BORDEAUX2-Bib. électronique (335229905) / SudocSudocFranceF

A small-area ecologic study of myocardial infarction, neighborhood deprivation, and sex: a Bayesian modeling approach.

International audienceBACKGROUND: Socioeconomic inequalities in the risk of coronary heart disease (CHD) are well documented for men and women. CHD incidence is greater for men but its association with socioeconomic status is usually found to be stronger among women. We explored the sex-specific association between neighborhood deprivation level and the risk of myocardial infarction (MI) at a small-area scale. METHODS: We studied 1193 myocardial infarction events in people aged 35-74 years in the Strasbourg metropolitan area, France (2000-2003). We used a deprivation index to assess the neighborhood deprivation level. To take into account spatial dependence and the variability of MI rates due to the small number of events, we used a hierarchical Bayesian modeling approach. We fitted hierarchical Bayesian models to estimate sex-specific relative and absolute MI risks across deprivation categories. We tested departure from additive joint effects of deprivation and sex. RESULTS: The risk of MI increased with the deprivation level for both sexes, but was higher for men for all deprivation classes. Relative rates increased along the deprivation scale more steadily for women and followed a different pattern: linear for men and nonlinear for women. Our data provide evidence of effect modification, with departure from an additive joint effect of deprivation and sex. CONCLUSIONS: We document sex differences in the socioeconomic gradient of MI risk in Strasbourg. Women appear more susceptible at levels of extreme deprivation; this result is not a chance finding, given the large difference in event rates between men and women

The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism.

International audienceGenetic diseases have been historically segregated into rare Mendelian disorders and common complex conditions. Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits. Here, we analysed data from the Genomics England 100,000 Genomes Project and from a cohort of 1313 individuals with albinism aiming to gain insights into the genetic architecture of this archetypal rare disorder. We investigated the contribution of protein-coding and regulatory variants both rare and common. We focused on TYR, the gene encoding tyrosinase, and found that a high-frequency promoter variant, TYR c.-301C>T [rs4547091], modulates the penetrance of a prevalent, albinism-associated missense change, TYR c.1205G>A (p.Arg402Gln) [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[-301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82). This genotype is also associated with reduced visual acuity and with increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants can increase diagnostic yield and can help inform genetic counselling in families with albinism