Showing papers by "Jean-Louis Mandel published in 2006"

BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus.

Abstract: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous ciliopathy. Although nine BBS genes have been cloned, they explain only 40-50% of the total mutational load. Here we report a major new BBS locus, BBS10, that encodes a previously unknown, rapidly evolving vertebrate-specific chaperonin-like protein. We found BBS10 to be mutated in about 20% of an unselected cohort of families of various ethnic origins, including some families with mutations in other BBS genes, consistent with oligogenic inheritance. In zebrafish, mild suppression of bbs10 exacerbated the phenotypes of other bbs morphants.

The Evolutionary Origin of Peroxisomes: An ER-Peroxisome Connection

Abstract: The peroxisome is an essential eukaryotic organelle, crucial for lipid metabolism and free radical detoxification, development, differentiation, and morphogenesis from yeasts to humans. Loss of peroxisomes invariably leads to fatal peroxisome biogenesis disorders in man. The evolutionary origin of peroxisomes remains unsolved; proposals for either a symbiogenetic or cellular membrane invagination event are unconclusive. To address this question, we have probed with a peroxisomal proteome, an "ensemble" of 19 representative eukaryotic complete genomes. Molecular phylogenetic and sequence comparison tools allowed us to identify four proteins as peroxisomal markers for unequivocal in silico peroxisome detection. We have then detected the Apicomplexa phylum as the first group of organisms devoid of peroxisomes, in the presence of mitochondria. Finally, we deliver evidence against a prokaryotic ancestor of peroxisomes: (1) the peroxisomal membrane is composed of purely eukaryotic bricks and is thus useful to trace the eukaryotes in their evolutionary paths and (2) the peroxisomal matrix protein import system shares mechanistic similarities with the endoplasmic reticulum/proteasome degradation process, indicating a common evolutionary history.

A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy.

Abstract: In eukaryotic cells, phosphoinositides are lipid second messengers important for many cellular processes and have been found dysregulated in several human diseases. X-linked myotubular (centronuclear) myopathy is a severe congenital myopathy caused by mutations in a phosphatidylinositol 3-phosphate (PtdIns3P) phosphatase called myotubularin, and mutations in dominant centronuclear myopathy (CNM) cases were identified in the dynamin 2 gene. The genes mutated in autosomal recessive cases of CNMs have not been found. We have identified a novel phosphoinositide phosphatase (hJUMPY) conserved through evolution, which dephosphorylates the same substrates as myotubularin, PtdIns3P and PtdIns(3,5)P(2), in vitro and ex vivo. We found, in sporadic cases of CNMs, two missense variants that affect the enzymatic function. One of these appeared de novo in a patient also carrying a de novo mutation in the dynamin 2 gene. The other missense (R336Q) found in another patient changes the catalytic arginine residue of the core phosphatase signature present in protein tyrosine/dual-specificity phosphatases and in phosphoinositide phosphatases and drastically reduces the enzymatic activity both in vitro and in transfected cells. The inheritance of the phenotype with regard to this variant is still unclear and could be either recessive with an undetected second allele or digenic. We propose that impairment of hJUMPY function is implicated in some cases of autosomal CNM and that hJUMPY cooperates with myotubularin to regulate the level of phosphoinositides in skeletal muscle.

Polyglutamine expansion causes neurodegeneration by altering the neuronal differentiation program

Abstract: Huntington's disease (HD) and spinocerebellar ataxia type 7 (SCA7) belong to a group of inherited neurodegenerative diseases caused by polyglutamine (polyQ) expansion in corresponding proteins. Transcriptional alteration is a unifying feature of polyQ disorders; however, the relationship between polyQ-induced gene expression deregulation and degenerative processes remains unclear. R6/2 and R7E mouse models of HD and SCA7, respectively, present a comparable retinal degeneration characterized by progressive reduction of electroretinograph activity and important morphological changes of rod photoreceptors. The retina, which is a simple central nervous system tissue, allows correlating functional, morphological and molecular defects. Taking advantage of comparing polyQ-induced degeneration in two retina models, we combined gene expression profiling and molecular biology techniques to decipher the molecular pathways underlying polyQ expansion toxicity. We show that R7E and R6/2 retinal phenotype strongly correlates with loss of expression of a large cohort of genes specifically involved in phototransduction function and morphogenesis of differentiated rod photoreceptors. Accordingly, three key transcription factors (Nrl, Crx and Nr2e3) controlling rod differentiation genes, hence expression of photoreceptor specific traits, are down-regulated. Interestingly, other transcription factors known to cause inhibitory effects on photoreceptor differentiation when mis-expressed, such as Stat3, are aberrantly re-activated. Thus, our results suggest that independently from the protein context, polyQ expansion overrides the control of neuronal differentiation and maintenance, thereby causing dysfunction and degeneration.

Pitfalls of homozygosity mapping: an extended consanguineous Bardet-Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism.

Abstract: The extensive genetic heterogeneity of Bardet-Biedl syndrome (BBS) is documented by the identification, by classical linkage analysis complemented recently by comparative genomic approaches, of nine genes (BBS1-9) that account cumulatively for about 50% of patients. The BBS genes appear implicated in cilia and basal body assembly or function. In order to find new BBS genes, we performed SNP homozygosity mapping analysis in an extended consanguineous family living in a small Lebanese village. This uncovered an unexpectedly complex pattern of mutations, and led us to identify a novel BBS gene (BBS10). In one sibship of the pedigree, a BBS2 homozygous mutation was identified, while in three other sibships, a homozygous missense mutation was identified in a gene encoding a vertebrate-specific chaperonine-like protein (BBS10). The single patient in the last sibship was a compound heterozygote for the above BBS10 mutation and another one in the same gene. Although triallelism (three deleterious alleles in the same patient) has been described in some BBS families, we have to date no evidence that this is the case in the present family. The analysis of this family challenged linkage analysis based on the expectation of a single locus and mutation. The very high informativeness of SNP arrays was instrumental in elucidating this case, which illustrates possible pitfalls of homozygosity mapping in extended families, and that can be explained by the rather high prevalence of heterozygous carriers of BBS mutations (estimated at one in 50 in Europeans).

BBS8 is rarely mutated in a cohort of 128 Bardet–Biedl syndrome families

Abstract: BBS8 is one of the eight genes identified to date for Bardet–Biedl syndrome (BBS)—an autosomal recessive condition associated with retinitis pigmentosa, obesity, polydactyly, cognitive impairment and kidney failure. The identification of BBS8 gave the key to the pathogenesis of the condition as a primary ciliary disorder. To date, only three families mutated in the BBS8 gene have been reported. Here, we report on three additional families with BBS8 mutations from a series of 128 BBS families. Two of the three families have homozygous mutations and one has a heterozygous mutation. Mutations in BBS8 probably account for only a minority of BBS families (2%), underlining the difficulty of genotyping heterogeneous conditions.

Exonic microdeletions in the X-linked PQBP1 gene in mentally retarded patients: a pathogenic mutation and in-frame deletions of uncertain effect

Abstract: Mutations in PQBP1 were recently identified in families with syndromic and non-syndromic X-linked mental retardation (XLMR) Clinical features frequently associated with MR were microcephaly and/or short stature The predominant mutations detected so far affect a stretch of six AG dinucleotides in the polar-amino-acid-rich domain (PRD), causing frameshifts in the fourth coding exon We searched for PQBP1 exon 4 frameshifts in 57 mentally retarded males in whom initial referral description indicated at least one of the following criteria: microcephaly, short stature, spastic paraplegia or family history compatible with XLMR, and in 772 mentally retarded males not selected for specific clinical features or family history We identified a novel frameshift mutation (23 bp deletion) in two half-brothers with specific clinical features, and performed prenatal diagnosis in this family We also found two different 21 bp in-frame deletions (c334-354del(21 bp) and c393-413del(21 bp)) in four unrelated probands from various ethnic origins, each deleting one of five copies of an imperfect seven amino-acid repeat Although such deletions have not been detected in 1180 X chromosomes from European controls, the c 334-354del(21 bp) was subsequently found in two of 477 Xs from Indian controls We conclude that pathogenic frameshift mutations in PQBP1 are rare in mentally retarded patients lacking specific associated signs and that the 21 bp in-frame deletions may be non-pathogenic, or alternatively could act subtly on PQBP1 function This touches upon a common dilemma in XLMR, that is, how to distinguish between mutations and variants that may be non-pathogenic or represent risk factors for cognitive impairment

Erratum: Corrigendum: BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus

Abstract: Nat. Genet. 38, 521–524 (2006). The name of author Eduardo D. Silva was misspelled in the original version of this paper. It is listed correctly above.

Syndrôme de Bardet-Biedl : une famille unique pour un gène majeur (BBS10)

Abstract: 901 M/S n° 11, vol. 22, novembre 2006 l’analyse de 10 000 SNP répartis sur l’ensemble du génome, représentant un gain d’informativité d’environ 8 fois par rapport aux 400 marqueurs microsatellites utilisés en général pour réaliser « un tour de génome »). Toutefois, au lieu d’identifier un seul locus, comme attendu pour une telle famille, nous avons trouvé deux zones d’intérêt : une première zone sur le chromosome 16 correspondant à la région du gène BBS2 (pour une fratrie) et une autre zone sur le chromosome 12 (pour 3 fratries), ne correspondant à aucun gène BBS connu (Figure 1B). Une mutation faux-sens a été identifiée dans BBS2 pour deux sœurs homozygotes dans la région correspondante en 16q21, mais cette mutation n’était pas présente chez les autres patients de cette famille. Ce premier résultat a confirmé une faille dans l’approche classique de cartographie par homozygotie [9]. > Décrit en 1920, le syndrome de Bardet-Biedl (BBS) (OMIM 209900) est une maladie autosomique récessive caractérisée par un cortège clinique comportant comme signes cliniques principaux : rétinopathie pigmentaire précoce, obésité, polydactylie, hypogonadisme, déficit cognitif variable et anomalies rénales (➜). Cette affection, a priori clairement définie sur le plan clinique, a été un des premiers exemples d’hétérogénéité génétique prouvée par cartographie génétique par homozygotie au début des années 1990. Récemment, il a été suggéré que l’hérédité du syndrome pouvait se démarquer de l’hérédité autosomique classique avec, pour certaines familles, la description de trois allèles mutés dans deux gènes BBS différents (hérédité oligogénique ou triallélique) [1] (➜), le troisième allèle induisant un effet épistatique sur le phénotype. Un gène modificateur interagissant avec les mutations des autres gènes BBS vient ainsi d’être décrit [2]. La physiopathogénie de la maladie a été révélée par la publication en 2003 du gène BBS8, identifié comme codant une protéine du centrosome ou du corpuscule basal impliquée dans la constitution du cil primitif [3]. Les cils primitifs, présents dans une grande majorité de nos cellules, sont impliqués dans l’exploration de l’environnement interne et externe de l’organisme par le biais de fonctions chimio-, photoet mécanosensorielles [4]. De plus, les cils jouent un rôle essentiel dans des étapes critiques du développement embryonnaire, et notamment dans le phénomène de polarité cellulaire planaire pour certains épithéliums, mais également dans d’autres tissus comme le tissu nerveux. Le syndrome BBS est maintenant classé comme une ciliopathie au même titre que les polykystoses rénales et les néphronophtises, le syndrome d’Alström, le syndrome orofaciodigital de type 1 et plus récemment les syndromes de Meckel et de Joubert (pour revue, voir [5, 6]). Fin 2005, 9 gènes avaient été identifiés (BBS de 1 à 9), ne rendant compte que de 50 % des patients. Le gène BBS1 est muté chez 20 % à 25 % des patients. Les gènes BBS de 2 à 9 ne sont retrouvés chacun mutés que dans un petit pourcentage de patients. Récemment, le gène BBS10 a été identifié par notre groupe et son impact majeur dans la maladie a été démontré [7]. Le gène BBS11, impliqué dans une seule famille (mutation faux-sens) [8], ne nous paraît pas parfaitement validé, d’autant plus qu’il a été également retrouvé muté dans une forme de myopathie progressive (LGM2H).

Corrigendum: BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus

Abstract: Corrigendum: BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus