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Biomedical subjects

C Moraine

Publications and source records attributed to C Moraine.

At least 19 recordsLinked to original sources
PubMed2001

MECP2 is highly mutated in X-linked mental retardation.

Following the recent discovery that the methyl-CpG binding protein 2 (MECP2) gene located on Xq28 is involved in Rett syndrome (RTT), a wild spectrum of phenotypes, including mental handicap, has been shown to be associated with mutations in MECP2. These findings, with the compelling genetic evidence suggesting the presence in Xq28 of additional genes besides RabGDI1 and FMR2 involved in non-specific X-linked mental retardation (MRX), prompted us to investigate MECP2 in MRX families. Two novel mutations, not found in RTT, were identified. The first mutation, an E137G, was identified in the MRX16 family, and the second, R167W, was identified in a new mental retardation (MR) family shown to be linked to Xq28. In view of these data, we screened MECP2 in a cohort of 185 patients found negative for the expansions across the FRAXA CGG repeat and reported the identification of mutations in four sporadic cases of MR. One of the mutations, A140V, which we found in two patients, has been described previously, whereas the two others, P399L and R453Q, are novel mutations. In addition to the results demonstrating the involvement of MECP2 in MRX, this study shows that the frequency of mutations in MECP2 in the mentally retarded population screened for the fragile X syndrome is comparable to the frequency of the CGG expansions in FMR1. Therefore, implementation of systematic screening of MECP2 in MR patients should result in significant progress in the field of molecular diagnosis and genetic counseling of mental handicap.

Adult↗
PubMed2000

Mapping of X chromosome inversion breakpoints [inv(X)(q11q28)] associated with FG syndrome: a second FG locus [FGS2]?

FG syndrome is an X-linked condition comprising mental retardation, congenital hypotonia, macrocephaly, distinctive facial changes, and constipation or anal malformations. In a linkage analysis, we mapped a major FG syndrome locus [FGS1] to Xq13, between loci DXS135 and DXS1066. The same data, however, clearly demonstrated genetic heterogeneity. Recently, we studied a French family in which an inversion [inv(X)(q12q28)] segregates with clinical symptoms of FG syndrome. This suggests that one of the breakpoints corresponds to a second FG syndrome locus [FGS2]. We report the results of fluorescence in situ hybridization analysis performed in this family using YACs and cosmids encompassing the Xq11q12 and Xq28 regions. Two YACs, one positive for the DXS1 locus at Xq11.2 and one positive for the color vision pigment genes and G6PD loci at Xq28, were found to cross the breakpoints, respectively. We postulate that a gene might be disrupted by one of the breakpoints.

Abnormalities, Multiple↗
PubMed2000

Missense mutation in PAK3, R67C, causes X-linked nonspecific mental retardation.

X-linked mental retardation is a very common condition that affects approximately 1 in 600 males. Despite recent progress, in most cases the molecular defects underlying this disorder remain unknown. Recently, a study using the candidate gene approach demonstrated the presence of mutations in PAK3 (p21-activating kinase) associated with nonspecific mental retardation. PAK3 is a member of the larger family of PAK genes. PAK proteins have been implicated as critical downstream effectors that link Rho-GTPases to the actin cytoskeleton and to MAP kinase cascades, including the c-Jun amino-terminal kinase (JNK) and p38. We screened 12 MRX pedigrees that map to a large region overlying Xq21-q24. Mutation screening of the whole coding region of the PAK3 gene was performed by using a combination of denaturing gradient gel electrophoresis and direct sequencing. We have identified a novel missense mutation in exon 2 of PAK3 gene (R67C) in MRX47. This confirms the involvement of PAK3 in MRX following the report of a nonsense mutation recently reported in MRX30. In the MRX47 family, all affected males show moderate to severe mental retardation. No seizures, statural growth deficiency, or minor facial or other abnormal physical features were observed. This mutation R67C is located in a conserved polybasic domain (AA 66-68) of the protein that is predicted to play a major role in the GTPases binding and stimulation of Pak activity.

Amino Acid Sequence↗
PubMed2000

Prenatal ultrasonographic diagnosis of the popliteal pterygium syndrome.

The prenatal ultrasound identification of a cleft lip and palate, equinovarus feet with severe lower limb malposition and genital abnormalities led to the prenatal diagnosis of popliteal pterygium syndrome in a pregnant mother suspected to have a mild expression of this autosomal dominant condition. However, in sporadic cases with lack of a family history for this rare syndrome, prenatal diagnosis may be difficult to ascertain.

Adult↗
PubMed2000

Subtle familial unbalanced translocation t(8;11)(p23.2;p15.5) in two fetuses with Beckwith-Wiedemann features.

We describe a subtle translocation t(8;11)(p23.2;p15.5) ascertained after two induced abortions in the same sibship because of the discovery of fetal hydrops on ultrasound examination. Initial cytogenetic studies performed on cultured amniotic fluid cells were considered as normal in both fetuses. High resolution banding analysis and FISH studies performed on the parents' chromosomes revealed a paternal translocation t(8;11)(p23.2;p15.5). Retrospective FISH analysis of both fetuses showed that they carried the same chromosomal imbalance including a distal monosomy 8pter and a distal trisomy 11pter. The phenotypes of the fetuses were re-examined and found to be compatible with Beckwith-Wiedemann syndromes (BWS). FISH analysis using an IGF2 probe demonstrated the presence of three copies of the IGF2 gene. This study highlights the value of searching for subtle chromosome rearrangements in families with recurrent unexplained multiple malformation syndromes discovered prenatally. Also, it contributes to a better delineation of the prenatal phenotype of BWS. Finally, it sheds new light on the aetiology of non-immune hydrops fetalis.

Adult↗
PubMed2000

A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation.

X-linked forms of mental retardation (MR) affect approximately 1 in 600 males and are likely to be highly heterogeneous. They can be categorized into syndromic (MRXS) and nonspecific (MRX) forms. In MRX forms, affected patients have no distinctive clinical or biochemical features. At least five MRX genes have been identified by positional cloning, but each accounts for only 0.5%-1.0% of MRX cases. Here we show that the gene TM4SF2 at Xp11.4 is inactivated by the X breakpoint of an X;2 balanced translocation in a patient with MR. Further investigation led to identification of TM4SF2 mutations in 2 of 33 other MRX families. RNA in situ hybridization showed that TM4SF2 is highly expressed in the central nervous system, including the cerebral cortex and hippocampus. TM4SF2 encodes a member of the tetraspanin family of proteins, which are known to contribute in molecular complexes including beta-1 integrins. We speculate that through this interaction, TM4SF2 might have a role in the control of neurite outgrowth.

Amino Acid Sequence↗
PubMed2000

Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation.

X-linked forms of mental retardation (XLMR) include a variety of different disorders and may account for up to 25% of all inherited cases of mental retardation. So far, seven X-chromosomal genes mutated in nonspecific mental retardation (MRX) have been identified: FMR2, GDI1, RPS6KA3, IL1RAPL, TM4SF2, OPHN1 and PAK3 (refs 2-9). The products of the latter two have been implicated in regulation of neural plasticity by controlling the activity of small GTPases of the Rho family. Here we report the identification of a new MRX gene, ARHGEF6 (also known as alphaPIX or Cool-2), encoding a protein with homology to guanine nucleotide exchange factors for Rho GTPases (Rho GEF). Molecular analysis of a reciprocal X/21 translocation in a male with mental retardation showed that this gene in Xq26 was disrupted by the rearrangement. Mutation screening of 119 patients with nonspecific mental retardation revealed a mutation in the first intron of ARHGEF6 (IVS1-11T-->C) in all affected males in a large Dutch family. The mutation resulted in preferential skipping of exon 2, predicting a protein lacking 28 amino acids. ARHGEF6 is the eighth MRX gene identified so far and the third such gene to encode a protein that interacts with Rho GTPases.

Base Sequence↗
PubMed2000

Systematic analysis of X-inactivation in 19XLMR families: extremely skewed profiles in carriers in three families.

It has been demonstrated in several X-linked disorders, both with and without mental retardation, that the X-inactivation process plays a significant role in the expression of X-linked diseases in females. Moreover, in some disorders extremely skewed inactivation of the X chromosome is constant in carriers, and this is thought to result from a proliferation or a survival advantage for cells expressing the normal allele at this locus over cells expressing the mutated allele. X-linked mental retardation (XLMR) is heterogeneous, and cloning and characterization of the mutated genes are in progress. XLMR can be expressed in carrier females but often with milder manifestations. We report the systematic study of the X-inactivation profile of obligate carriers and other females in 19 multiplex XLMR pedigrees, using leucocyte-extracted DNA. Extremely skewed profiles were observed in carriers in three of 19 families.

Dosage Compensation, Genetic↗
PubMed2000

Severe cognitive impairment in DMD: obvious clinical indication for Dp71 isoform point mutation screening.

Duchenne muscular dystrophy is associated with variable degrees of selective cognitive defect with lower scores for verbal intelligence and reading abilities. A number of findings have shown that rearrangements located in the second part of the gene seem to be preferentially associated with cognitive impairment. Several dystrophin transcripts are expressed in the brain. The more distal of them, Dp71, is predominant. We have carried out a mutational analysis of Dp71 transcript in 12 DMD patients severely, mildly or not retarded, all without detectable deletion or duplication. We have detected five point mutations causing Dp71 premature translation termination. All were found among the more severely mentally retarded patients of this group (VIQ < 50 and/or no reading acquisition).

Adolescent↗
PubMed2000

First description of germline mosaicism in familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy is a genetically and phenotypically heterogeneous disease caused by mutations in seven sarcomeric protein genes. It is known to be transmitted as an autosomal dominant trait with rare de novo mutations.A French family in which two members are affected by hypertrophic cardiomyopathy was clinically screened with electrocardiography and echocardiography. Genetic analyses were performed on leucocyte DNA by haplotype analysis with microsatellite markers at the MYH7 locus and mutation screening by single strand conformation polymorphism analysis. Two subjects exhibited severe hypertrophic cardiomyopathy. A mutation in the MYH7 gene was found in exon 14 (Arg453Cys). The two affected patients were carriers of the mutation, which was not found in the circulating lymphocytes of their parents. Haplotype analysis at the MYH7 locus with two intragenic microsatellite markers (MYOI and MYOII) and the absence of the mutation in the father's sperm DNA suggested that the mutation had been inherited from the mother. However, it was not found in either her fibroblasts or hair. This is the first description of germline mosaicism shown by molecular genetic analysis in an autosomal dominant disorder and more especially in hypertrophic cardiomyopathy. This mosaicism had been inherited from the mother but did not affect her somatic cells. Such a phenomenon might account for some de novo mutations in familial hypertrophic cardiomyopathy.

Adolescent↗
PubMed1999

A novel ribosomal S6-kinase (RSK4; RPS6KA6) is commonly deleted in patients with complex X-linked mental retardation.

Large deletions in Xq21 often are associated with contiguous gene syndromes consisting of X-linked deafness type 3 (DFN3), mental retardation (MRX), and choroideremia (CHM). The identification of deletions associated with classic CHM or DFN3 facilitated the positional cloning of the underlying genes, REP-1 and POU3F4, respectively, and enabled the positioning of the MRX gene in between these genes. Here, we report the cloning and characterization of a novel gene, ribosomal S6-kinase 4 (RSK4; HGMW-approved symbol RPS6KA6), which maps in the MRX critical region. RSK4 is completely deleted in eight patients with the contiguous gene syndrome including MRX, partially deleted in a patient with DFN3 and present in patients with an Xq21 deletion and normal intellectual abilities. RSK4 is most abundantly expressed in brain and kidney. The predicted protein of 746 amino acids shows a high level of homology to three previously isolated members of the human RSK family. RSK2 is involved in Coffin-Lowry syndrome and nonspecific MRX. The localization of RSK4 in the interval that is commonly deleted in mentally retarded males together with the high degree of amino acid identity with RSK2 suggests that RSK4 plays a role in normal neuronal development. Further mutation analyses in males with X-linked mental retardation must prove that RSK4 is indeed a novel MRX gene.

Amino Acid Sequence↗
PubMed1999

Splenogonadal fusion limb defect syndrome: report of five new cases and review.

Splenogonadal fusion (SGF) is a rare congenital malformation in which the spleen is abnormally connected to the gonad. SGF may occur as an isolated condition or may be associated with other malformations, especially with terminal limb defects in what is called splenogonadal fusion limb defect (SGFLD) syndrome. In this article, we report on 5 new cases of SGFLD and we review the 25 cases reported since 1889. Most cases reviewed here have a combination of severe limb and oro-mandibular defects, suggesting that SGFLD may be related to the broader group of Hanhart complex. In addition, several cases have limb malformations and facial anomalies, which suggest that SGFLD overlaps with both femur-fibula-ulna dysostosis and femoral-facial syndrome. The hypothesis of a vascular disruptive event, occurring between the 5th and the 7th weeks of gestation, could explain the limb defects, the mandibular hypoplasia, and the fusion of the spleen to the gonad observed in SGFLD. However, this heterogenous and polytopic condition could also be the consequence of a primary field defect. All the cases to date reported have been sporadic and the recurrence risk is probably low. However, a recent case of Roberts syndrome with SGF was reported that suggests careful examination of chromosomal status.

Abnormalities, Multiple↗
PubMed1999

Paracentric inversion of the X chromosome [inv(X)(q12q28)] in familial FG syndrome.

FG syndrome is an X-linked incomplete recessive condition comprising mental retardation, congenital hypotonia, macrocephaly, a distinctive facial appearance, and constipation or anal malformations. Here, we report on a chromosome X inversion [inv(X)(q12q28)] in a boy with FG syndrome and in his mentally retarded maternal uncle, and we discuss the possible involvement of this paracentric inversion in the FG syndrome.

Abnormalities, Multiple↗