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Biomedical subjects

J Boué

Publications and source records attributed to J Boué.

At least 19 recordsLinked to original sources
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↗
PubMed1998

Novel and recurrent tyrosine aminotransferase gene mutations in tyrosinemia type II.

Tyrosinemia type II (Richner-Hanhart syndrome, RHS) is a disorder of autosomal recessive inheritance characterized by keratitis, palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels. The disease results from deficiency in hepatic tyrosine aminotransferase (TAT). We have previously described one deletion and six different point mutations in four RHS patients. We have now analyzed the TAT genes in a further seven unrelated RHS families from Italy, France, the United Kingdom, and the United States. We have established PCR conditions for the amplification of all twelve TAT exons and have screened the products for mutations by direct sequence analysis or by first performing single-strand conformation polymorphism analysis. We have thus identified the presumably pathological mutations in eight RHS alleles, including two nonsense mutations (R57X, E411X) and four amino acid substitutions (R119W, L201R, R433Q, R433W). Only the R57X mutation, which was found in one Scottish and two Italian families, has been previously reported in another Italian family. Haplotype analysis indicates that this mutation, which involves a CpG dinucleotide hot spot, has a common origin in the three Italian families but arose independently in the Scottish family. Two polymorphisms have also been detected, viz., a protein polymorphism, P15S, and a silent substitution S103S (TCG-->TCA). Expression of R433Q and R433W demonstrate reduced activity of the mutant proteins. In all, twelve different TAT gene mutations have now been identified in tyrosinemia type II.

Adult↗
PubMed1997

Gene for nonspecific X-linked mental retardation (MRX 47) is located in Xq22.3-q24.

We describe a large family with nonspecific X-linked mental retardation (MRX 47). An X-linked recessive transmission is suggested by the inheritance from the mothers in two generations of a moderate to severe form of mental retardation in six males, without any specific clinical findings. Two point linkage analysis demonstrated significant linkage between the disorder and two markers in Xq23 (Zmax = 3.75, theta = 0). Multipoint linkage analyses confirmed the significant linkage with a maximum lod score (Z = 3.96, theta = 0) at DXS1059. Recombination events observed with the flanking markers DXS1105 and DXS8067 delineate a 17 cM interval. This interval overlaps with several loci of XLMR disorders previously localized in Xq23-q24, which are reviewed herein.

Chromosome Mapping↗
PubMed1997

A gene for dominant nonspecific X-linked mental retardation is located in Xq28.

A large family (MRX48) with a nonspecific X-linked mental retardation condition is described. An X-linked semidominant inheritance is suggested by the segregation in three generations of a moderate to severe mental retardation in seven males and by a milder intellectual impairment in two females, without any specific clinical, radiological, or biological feature. Two-point linkage analysis demonstrated significant linkage between the disorder and several markers in Xq28 (maximum LOD score [Zmax] = 2.71 at recombination fraction [theta] = 0); multipoint linkage analyses confirmed the significant linkage with a Zmax of 3.3 at theta = 0, at DXS1684. A recombination event observed with the flanking marker DXS8011 delineates a locus between this marker and the telomere. The approximate length of this locus is 8-9 cM, corresponding to 5.5-6 Mb. In an attempt to explain the variable intellectual impairment in females, we examined X-chromosome inactivation in all females of the family. Inactivation patterns in lymphocytes were random or moderately skewed, and no correlation between the phenotypic status and a specific inactivation pattern was observed. The interval of assignment noted in this family overlaps with five MRX loci previously reported in Xq28.

Adult↗
PubMed1997

[Genetics of Fragile X syndrome and its prevention].

The fragile X syndrome is the most common inherited form of mental retardation. Its prevalence is estimated to be one in 1000-4000 males and one in 2000-6000 females, depending of the region. A large canadian population study in Quebec has shown a frequency of 1/260 carrier women. The fragile X syndrome was the first disease shown to be associated with "dynamic mutations", caused by an amplification of an unstable DNA sequence transmitted from generations to generations till a pathologic expression: mental retardation. The prevention is possible by a specific DNA analysis of patients and male and female carriers. It is possible to detect the mutation or the premutation in pregnant women and to propose a prenatal diagnosis by molecular study on chorionic villi samples or cultivated amniocytes.

Female↗
PubMed1996

Parental origin and mechanisms of formation of three cases of 12p tetrasomy.

Pallister-Killian syndrome is a clinically recognizable syndrome characterized by tissue-limited mosaicism for an extra 12p isochromosome. Very little is known about the underlying mechanism of this rare rearrangement. Microsatellite markers were studied from three fetuses with Pallister-Killian syndrome and their parents to determine the parent of origin and the cell division yielding the additional isochromosome. In two cases the isochromosome contained the same allele(s) as a normal transmitted chromosome 12, one paternal and one maternal in origin. A third case showed inheritance of two different maternal alleles, indicating that at least one meiotic error was involved in the ultimate formation of the extra isochromosome.

Abnormalities, Multiple↗
PubMed1995

Screening of CYP21 gene mutations in 129 French patients affected by steroid 21-hydroxylase deficiency.

The frequency of 12 different mutations of the steroid 21-hydroxylase gene (CYP21) was investigated in 129 French patients affected by congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency. Eighty-nine percent of the CAH chromosomes were characterized. The most frequent mutations were a C-G substitution in intron 2, the deletion of the CYP21 gene and a T-A substitution in exon 4 in the severe form of the disease, and a G-T substitution in exon 7 in the nonclassic form. The correlation between the genotypes and the clinical forms of the disease showed marked variation in the phenotype from a single genotype, suggesting that individual variation and undetected additional mutations on the same CAH chromosome accounted for the phenotype. In 65 informative meioses of CAH families, no de novo mutation was found.

Adrenal Hyperplasia, Congenital↗
PubMed1994

Transition from normal to premutated alleles in fragile X syndrome results from a multistep process.

In fragile X syndrome, the most common cause of inherited mental retardation, phenotypic expression has been linked to a region containing a repetitive sequence, (CGG)n, that appears to lengthen dramatically in fragile X patients and to show length variation in normal individuals. In order to investigate possible mechanisms responsible for further expansion of CGG in the normal population, we selected 31 normal unrelated X chromosomes carrying either the high-risk DX204-AC155 or DX196-AC151 haplotypes, as defined by the flanking microsatellites, DXS548 and FRAXAC2. Nearly 100% of CGGs with more than 35 repeats were found on DX204-AC155 haplotypes, with a mean length significantly higher and much more variable than in normal individuals carrying other haplotypes including the high-risk haplotype DX196-AC151. These findings suggest that the transition from the normal to the abnormal range occurs by a multistep process, a primary event, such as unequal crossing-over, leading to increased size and moderate instability of the repeat, and from which DNA polymerase slippage could lead to recurrent premutations. Our results also suggest that the upper limit of the normal range is roughly 35 repeats in the fragile X gene. The 36-54 repeats range would define an intermediate allele only observed, up to now, in DX204-AC155 fragile X chromosomes.

Analysis of Variance↗
PubMed1993

Molecular analysis of a ring chromosome X in a family with fragile X syndrome.

The phenotypically normal sister of a patient affected by fragile X syndrome was referred for genetic counselling and was found to carry a mosaic karyotype 46,X,r(X)/45,X. Because the probability of the simultaneous chance occurrence of fragile X syndrome and a ring chromosome X in the same family is very low, we postulated that the breakpoint of the ring chromosome X originated in the cytogenetic break in Xq27.3 responsible for fragile X syndrome. In order to determine the relative positions of the breakpoint on the ring chromosome X and the (CGG)n unstable sequence responsible for the fragile X mutation, we used molecular markers to analyse the telomeric regions of chromosome X in this family. The results showed that the ring chromosome X was the maternal fragile X chromosome and that the telomeric deletion on the long arm encompassed the (CGG)n sequence. This suggests that the cytogenetic break in Xq27.3 is distinct from the unstable (CGG)n sequence, or that the break followed by the end-to-end fusion creating the ring chromosome was not completely conservative. Analysis of DNA markers on the short arm of chromosome X evidenced a deletion of a large part of the pseudoautosomal region, allowing us to position the genes involved in stature and in some syndromes associated with telomeric deletions of Xp on the proximal side of the pseudoautosomal region.

Adult↗
PubMed1993

General cystic fibrosis mutations are usually missense mutations affecting two specific protein domains and associated with a specific RFLP marker haplotype.

Some 250 different mutations have so far been screened in the cystic fibrosis (CF) gene. The 50 nonsense, 33 splicing and 60 frameshift mutations are randomly distributed within the gene, unlike the 107 missense mutations or amino acid deletions. A large excess of missense mutations affects the exons encoding the first transmembrane (MS1) and first ATP-binding fold (NBF1) domains. Sixty-four of the 107 missense mutations may be classified as private, demic, local and general mutations on the basis of their geographic distribution in Europe. Private and demic mutations are randomly distributed within the gene; local and general mutations are not. It is well known that some RFLP markers are in linkage disequilibrium with some mutations. Private, demic and local mutations are randomly associated with each class of RFLP haplotypes. In contrast, general mutations, frequent and infrequent, are not randomly associated with RFLP markers. General mutations usually affect a specific part of the gene and are more likely to be associated with a specific RFLP marker. This suggests the existence of selective factors favoring these mutations, a hypothesis formerly postulated as a possible cause of the high frequency of the disease.

Cystic Fibrosis↗
PubMed1993

Linkage disequilibrium between the fragile X mutation and two closely linked CA repeats suggests that fragile X chromosomes are derived from a small number of founder chromosomes.

In order to investigate the origin of mutations responsible for the fragile X syndrome, two polymorphic CA repeats, one at 10 kb (FRAXAC2) and the other at 150 kb (DXS548) from the mutation target, were analyzed in normal and fragile X chromosomes. Contrary to observations made in myotonic dystrophy, fragile X mutations were not strongly associated with a single allele at the marker loci. However, significant differences in allelic and haplotypic distributions were observed between normal and fragile X chromosomes, indicating that a limited number of primary events may have been at the origin of most present-day fragile X chromosomes in Caucasian populations. We propose a putative scheme with six founder chromosomes from which most of the observed fragile X-linked haplotypes can be derived directly or by a single event at one of the marker loci, either a change of one repeat unit or a recombination between DXS548 and the mutation target. Such founder chromosomes may have carried a number of CGG repeats in an upper-normal range, from which recurrent multistep expansion mutations have arisen.

Alleles↗
PubMed1992

[Accidental ultrasonographic disclosure of isolated intra-abdominal fetal hyperechogenicity. Apropos of a series of 87 cases].

Having seen 87 cases we will now attempt to refine the management to be carried out when intra-abdominal hyperechogenic masses are found in the fetus. Before the 20th week of amenorrhoea (47 cases) amniocentesis can be used to study the digestive enzymes to determine the fetal karyotype. The normal results for intestinal enzymes makes it possible to rule out fetal cystic fibrosis. Three karyotype abnormalities were found in this series. After the 20th week (40 cases) intestinal enzymes cannot be interpreted. The diagnosis of cystic fibrosis then must rely on Delta F 508 mutation; but the absence of this mutation does not exclude cystic fibrosis. When ultrasound signs of intra-abdominal hyperechogenicity are found the diagnosis of cystic fibrosis should not be thought of first, because in this series the majority of fetuses who had this sign were born without any malformation. Four cases of cystic fibrosis that were confirmed have been found but equally there were other serious malformations, three chromosome abnormalities, four intestinal atresias, ten unexplained intra-uterine deaths and one case of biliary duct atresia.

Amniotic Fluid↗
PubMed1992

Prenatal diagnosis of Niemann-Pick type C disease: current strategy from an experience of 37 pregnancies at risk.

Thirty-seven pregnancies at risk for Niemann-Pick type C disease were monitored by study of cultured amniotic fluid cells (8 cases) or chorionic villus cells (29 cases) in 23 couples over the period 1984-91. An early protocol combined determination of sphingomyelinase activity with electron microscopy. The current strategy, based on the demonstration of specific abnormalities in intracellular processing of exogenous cholesterol, combines the study of the early phase (first 6 h) of LDL-induced cholesteryl ester formation and the histochemical evaluation (filipin staining after 24 h of LDL uptake) of the LDL-induced accumulation of unesterified cholesterol. Thirteen fetuses were predicted to be affected. Confirmation of the diagnosis was made by study of cholesterol processing in fetal skin fibroblast cultures and/or by demonstration of a characteristic lipid storage in fetal liver, already present at 14 w gestation. Definition of the biochemical phenotype (classical, variant, or intermediate) of the index case, with regard to cholesterol-processing abnormalities, is an absolute prerequisite to adequate genetic counseling in a given family. Prenatal diagnosis has now proved a safe procedure in the predominant (approximately 85%) group of families with the classical phenotype.

Cells, Cultured↗
PubMed1991

Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation.

BACKGROUND: The fragile X syndrome, the most common form of inherited mental retardation, is caused by mutations that increase the size of a specific DNA fragment of the X chromosome (in Xq27.3). Affected persons have both a full mutation and abnormal DNA methylation. Persons with a smaller increase in the size of this DNA fragment (a premutation) have little or no risk of retardation but are at high risk of having affected children or grandchildren. The passage from premutation to full-mutation status occurs only with transmission from the mother. We have devised a method of identifying carriers of these mutations by direct DNA analysis. METHOD: We studied 511 persons from 63 families with the fragile X syndrome. Mutations and abnormal methylation were detected by Southern blotting with a probe adjacent to the mutation target. Analysis of EcoRI and EagI digests of DNA distinguished clearly in a single test between the normal genotype, the premutation, and the full mutation. RESULTS: DNA analysis unambiguously established the genetic status at the fragile X locus for all samples tested. This method was much more powerful and reliable than cytogenetic testing or segregation studies with closely linked polymorphic markers. The frequency of mental retardation in persons with premutations was similar to that in the general population, whereas all 103 males and 31 of 59 females with full mutations had mental retardation. About 15 percent of those with full mutations had some cells carrying only the premutation. All the mothers of affected children were carriers of either a premutation or a full mutation. CONCLUSIONS: Direct diagnosis by DNA analysis is now an efficient and reliable primary test for the diagnosis of the fragile X syndrome after birth, as well as for prenatal diagnosis and genetic counseling.

Blotting, Southern↗
PubMed1991

Pelizaeus-Merzbacher disease: a valine to phenylalanine point mutation in a putative extracellular loop of myelin proteolipid.

In the central nervous system, myelin proteolipid protein isoforms (PLP and DM20) play an essential structural role in myelination. It has been shown in several species that myelination is impaired by molecular defects resulting from single base mutations in the PLP gene. We have used DNA amplification by polymerase chain reaction to study the PLP gene coding regions from 17 patients in 15 unrelated families with similar Pelizaeus-Merzbacher phenotype. In one case amplification of peripheral nerve PLP/DM20 cDNAs revealed that a silent T----C transition was unrelated to the disease. In one family a nonsilent mutation was identified that leads to a phenylalanine substitution for valine-218 in PLP/DM20 proteins. We investigated the inheritance of the mutant allele in 19 subjects of this four-generation family and found a strict cosegregation of the Phe218 substitution with transmission and expression of the disease. The effect of the Val218----Phe mutation is discussed in the frame of a recently suggested topological model of PLP/DM20, according to which Val218 is part of an extracellular loop that connects the last two of four membrane-spanning alpha-helices.

Animals↗
PubMed1991

Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome.

The fragile X syndrome, a common cause of inherited mental retardation, is characterized by an unusual mode of inheritance. Phenotypic expression has been linked to abnormal cytosine methylation of a single CpG island, at or very near the fragile site. Probes adjacent to this island detected very localized DNA rearrangements that constituted the fragile X mutations, and whose target was a 550-base pair GC-rich fragment. Normal transmitting males had a 150- to 400-base pair insertion that was inherited by their daughters either unchanged, or with small differences in size. Fragile X-positive individuals in the next generation had much larger fragments that differed among siblings and showed a generally heterogeneous pattern indicating somatic mutation. The mutated allele appeared unmethylated in normal transmitting males, methylated only on the inactive X chromosome in their daughters, and totally methylated in most fragile X males. However, some males had a mosaic pattern. Expression of the fragile X syndrome thus appears to result from a two-step mutation as well as a highly localized methylation. Carriers of the fragile X mutation can easily be detected regardless of sex or phenotypic expression, and rare apparent false negatives may result from genetic heterogeneity or misdiagnosis.

Base Composition↗