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Biomedical subjects

C Junien

Publications and source records attributed to C Junien.

At least 19 recordsLinked to original sources
PubMed1995

Genetic linkage heterogeneity in myotubular myopathy.

Myotubular myopathy is a severe congenital disease inherited as an X-linked trait (MTM1; McKusick 31040). It has been mapped to the long arm of chromosome X, to the Xq27-28 region. Significant linkage has subsequently been established for the linkage group comprised of DXS304, DXS15, DXS52, and F8C in several studies. To date, published linkage studies have provided no evidence of genetic heterogeneity in severe neonatal myotubular myopathy (XLMTM). We have investigated a family with typical XLMTM in which no linkage to these markers was found. Our findings strongly suggest genetic heterogeneity in myotubular myopathy and indicate that great care should be taken when using Xq28 markers in linkage studies for prenatal diagnosis and genetic counseling.

Chromosome Mapping↗
PubMed1994

A second locus for Marfan syndrome maps to chromosome 3p24.2-p25.

Marfan syndrome (MFS) is an autosomal dominant connective-tissue disorder characterized by skeletal, ocular and cardiovascular defects of highly variable expressivity. The diagnosis relies solely on clinical criteria requiring anomalies in at least two systems. By excluding the chromosome 15 disease locus, fibrillin 1 (FBN1), in a large French family with typical cardiovascular and skeletal anomalies, we raised the issue of genetic heterogeneity in MFS and the implication of a second locus (MFS2). Linkage analyses, performed in this family, have localized MFS2 to a region of 9 centiMorgans between D3S1293 and D3S1283, at 3p24.2-p25. In this region, the highest lod score was found with D3S2336, of 4.89 (theta = 0.05). By LINKMAP analyses, the most probable position for the second locus in MFS was at D3S2335.

Adult↗
PubMed1993

Pericentric intrachromosomal insertion responsible for recurrence of del(11)(p13p14) in a family.

The combined use of qualitative and quantitative analysis of 11p13 polymorphic markers together with chromosomal in situ suppression hybridization (CISS) with biotin labeled probes mapping to 11p allowed us to characterize a complex rearrangement segregating in a family. We detected a pericentric intrachromosomal insertion responsible for recurrence of del(11)(p13p14) in the family: an insertion of brand 11p13-p14 carrying the genes for predisposition to Wilms' tumor, WT1, and for aniridia, AN2, into the long arm of chromosome 11 in 11q13-q14. Asymptomatic balanced carriers were observed over three generations. Classical cytogenetics had failed to detect this anomaly in the balanced carriers, who were first considered to be somatic mosaics for del(11)(p13). Two of these women gave birth to children carrying a deleted chromosome 11, most likely resulting from the loss of the 11p13 band inserted in 11q. Although in both cases the deletion encompassed exactly the same maternally inherited markers, there was a wide variation in clinical expression. One child, with the karyotype 46,XY, del(11)(p13p14), presented the full-blown WAGR syndrome with aniridia, mental retardation, Wilms' tumor, and pseudohermaphroditism, but also had proteinuria and glomerular sclerosis reminiscent of Drash syndrome. In contrast, the other one, a girl with the karyotype 46,XX,del(11)(p13), only had aniridia. Although a specific set of mutational sites has been observed in Drash patients, these findings suggest that the loss of one copy of the WT1 gene can result in similar genital and kidney abnormalities.

Child↗
PubMed1993

Physical and genetic mapping of the dipeptidase gene DPEP1 to 16q24.3.

We report the subregional physical and genetic mapping on chromosome 16q of a cDNA clone selected as a potential tumor/growth suppressor sequence. By DNA sequencing and RNA expression pattern, this clone was identified as part of the renal dipeptidase gene (DPEP1). Using somatic cell hybrids carrying either different human chromosomes or chromosome 16 segments, we confirm and refine the physical mapping of DPEP1 to the chromosome 16 subregion q24.3. Two RFLPs, a biallelic polymorphism detected by TaqI and a VNTR detected by BamHI, EcoRI, and BglII, are described. Using the VNTR polymorphism, DPEP1 was shown to be linked to D16S7 with a maximum lod score of 5.8 at a recombination fraction of 0.03.

Animals↗
PubMed1993

Myotonic dystrophy: absence of CTG enlarged transcript in congenital forms, and low expression of the normal allele.

Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease. The mutation has been identified as an unstable trinucleotide CTG repeat in a sequence encoding a putative cAMP-dependent protein kinase. The CTG repeat varies in length between affected siblings, and generally increases through generations in parallel with increasing severity of the disease. Congenital myotonic dystrophy, which represents the most severe phenotype, is exclusively maternally inherited. In this report, we show, by Northern blot analysis, that no mutated enlarged transcript is detectable in a 20-week-old DM fetus and in two congenitally affected infants. Furthermore, in skeletal and cardiac muscle of the DM fetus, we observed by RNA analysis, including Northern blot and RT-PCR, an unexpectedly low expression of the paternal wild type allele. Varying degrees of expression of the mutant and/or the normal allele might therefore account for the characteristic features of the congenital form and the extreme variability of the disease.

Alleles↗
PubMed1992

Diagnosis of Duchenne and Becker muscular dystrophies by polymerase chain reaction. A multicenter study.

OBJECTIVE--To assess the efficiency, reliability, and ease of use of DNA diagnosis for Duchenne and Becker muscular dystrophies (DMD/BMD) using the polymerase chain reaction (PCR). DESIGN--DNA from the patients was screened for deletion mutations using multiplex PCR, and the results were compared with those obtained by Southern blot analysis. The PCR multiplex reaction detects nine specific "hot-spot" exons in the dystrophin gene while the Southern analysis detects 66 specific dystrophin gene restriction fragments. The multiplex reaction requires 50-fold less DNA than Southern analysis and thus is considerably more sensitive. SETTING--Fourteen university-affiliated and private genetic disease diagnostic laboratories. PATIENTS--Male patients with clinical signs of DMD/BMD. Cases were selected for analysis randomly, without knowledge of whether a deletion was present within the dystrophin gene. MAIN OUTCOME MEASURES--The percentage of cases that were detectable by multiplex PCR in comparison with Southern analysis, the frequency, extent, and location of the detected deletion mutations. In some cases, duplication mutations were monitored. RESULTS--The accuracy of a single PCR multiplex amplification (nine exons) was compared with Southern analysis with 10 cDNA probes that cover the full length of the gene. The multiplex PCR analytic method detected 82% of those deletions detected by Southern analysis methods. In one of 745 analyses, the multiplex method suggested a single exon deletion, which was not confirmed by Southern analysis, representing a false-positive rate of 0.013%. CONCLUSIONS--Multiplex PCR represents a sensitive and accurate method for deletion detection of 46% of all cases of DMD/BMD. The method requires 1 day for analysis, is easy to perform, and does not use radioactive tracers. As such, multiplex PCR represents an efficient and rapid method for prenatal or postnatal diagnosis of DMD/BMD.

Blotting, Southern↗
PubMed1992

Screening for new mutations in the LDL receptor gene in seven French familial hypercholesterolemia families by the single strand conformation polymorphism method.

To investigate the molecular basis of familial hypercholesterolemia (FH) in France, we applied the single strand conformation polymorphism (SSCP) method to the promoter region and the 18 exons of the low density lipoprotein receptor (LDLR) gene. Seven probands, 4 heterozygotes, 2 compound heterozygotes, and 1 homozygote, belonging to FH families were tested. In all cases, previous genetic analysis and/or LDL receptor fibroblast assay had shown that the disease was due to defects in the LDLR gene. Out of the nine mutations expected, one nonsense mutation in exon 2 and six missense mutations were identified in exons 3, 6, 8, 11, and 15. Two of the latter were found in exon 6. In each family, cosegregation of the base substitution and the disease was observed. Ninety-five control subjects were screened for the presence of the six missense mutations. None was detected, implying that the mutations identified are deleterious. Our results indicate that the SSCP analysis of amplified genomic DNA fragments can be successfully used to rapidly screen mutation containing exons in large genes. Furthermore, all these mutations are newly described and demonstrate heterogeneity of LDLR gene mutations responsible for FH in the French population, as in other reported Caucasian populations.

Amino Acid Sequence↗
PubMed1992

Beckwith-Wiedemann syndrome, tumourigenesis and imprinting.

The concurrent development of cytogenetic, clinical, genetic and molecular studies has led to the recognition that the different hereditary and non-hereditary forms of the Beckwith-Wiedemann syndrome and associated tumours result from an imbalance between maternal and paternal alleles. The most exciting development in the past year was the discovery of uniparental paternal disomy and the increased understanding, arising from studies in the mouse and in hereditary cases, of the role possibly played by imprinting and somatic mosaicism in partial and complete expression of this complex syndrome.

Alleles↗
PubMed1992

A linkage map of 10 loci flanking the Marfan syndrome locus on 15q: results of an International Consortium study.

Members of an International Consortium for Linkage Analysis of the Marfan Syndrome (MFS1) have pooled data for joint analysis in an attempt to determine the precise location of the MFS1 gene and the order of 10 DNA markers on 15q. Five laboratories performed a total of 2111 genotypes in 22 families consisting of 225 affected and 248 normal subjects. For each marker a mean of 98 meioses was informative. D15S48 and D15S1 were identified as the closest linked markers with 99% upper confidence intervals of 12% and 13% respectively. We have used the CRI-MAP program to construct the most likely order as: D15S24-D15S25-D15S1-MFS1-D15S48-D15S49+ ++-(D15S45/S51)-(D15S29/S38). Placement of D15S2 in relation to -D15S1-D15S48- cannot be determined with certainty. The genetic map of these markers extends 53.6 cM in males and 65.0 cM in females with a sex averaged map of 60.7 cM. The sex difference was statistically significant (p = 0.005). Linkage heterogeneity between 22 MFS1 families was documented (p = 0.009) necessitating the exclusion of one family from the analysis. However, comparison of the remaining 21 families for two point and multipoint lod scores showed no evidence for linkage heterogeneity of the MFS1 locus.

Chromosome Mapping↗
PubMed1992

Beckwith-Wiedemann syndrome: a demonstration of the mechanisms responsible for the excess of transmitting females.

Beckwith-Wiedemann syndrome (BWS) is often associated with embryonal tumours (nephroblastoma, adrenocortical carcinoma, hepatoblastoma, and rhabdomyosarcoma). Several pedigrees have been reported strongly suggesting autosomal dominant inheritance and an excess of transmitting females was noticed in these families. We confirmed this excess using 19 published pedigrees and showed that this excess was for two reasons: first, reduced fecundity in affected males compared to females in a ratio of 1:4.6, and, second, a smaller risk of being affected in a ratio of 1:3 for subjects having inherited the gene from their father. These latter findings suggest genomic imprinting. Furthermore, considering these results together with other observations, such as the parental origin of the 15p15.5 duplication and the existence of uniparental disomy in some sporadic cases, we propose that overgrowth in BWS patients and malignant proliferation in associated tumours reflect an imbalance between paternal and maternal alleles.

Beckwith-Wiedemann Syndrome↗
PubMed1991

Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.

Denys-Drash syndrome is a rare human condition in which severe urogenital aberrations result in renal failure, pseudohermaphroditism, and Wilms' tumor (nephroblastoma). To investigate its possible role, we have analyzed the coding exons of the Wilms' tumor suppressor gene (WT1) for germline mutations. In ten independent cases of Denys-Drash syndrome, point mutations in the zinc finger domains of one WT1 gene copy were found. Nine of these mutations are found within exon 9 (zinc finger III); the remaining mutation is in exon 8 (zinc finger II). These mutations directly affect DNA sequence recognition. In two families analyzed, the mutations were shown to arise de novo. Wilms' tumors from three individuals and one juvenile granulosa cell tumor demonstrate reduction to homozygosity for the mutated WT1 allele. Our results provide evidence of a direct role for WT1 in Denys-Drash syndrome and thus urogenital system development.

Acute Kidney Injury↗
PubMed1991

Uniparental paternal disomy in a genetic cancer-predisposing syndrome.

The 11p15.5 region of human chromosome 11 seems to contain a locus or loci involved in congenital overgrowth anomalies as well as in the genesis of many tumours associated with the Beckwith-Wiedemann syndrome (BWS). Given the unusual differential parental allele involvement in the different aetiological forms of BWS and the loss of maternal alleles in associated tumours, we have now used 11p15.5 markers to determine the parental origin of chromosome 11 in eight sporadic cases of BWS. Probands in three informative families had uniparental paternal disomy for region 11p15.5. Further, an overall greatly increased frequency of homozygosity for several 11p15.5 markers in 21 sporadic BWS patients suggests that isodisomy probably accounts for an even higher proportion of BWS sporadic cases. This demonstrates that uniparental paternal disomy can be associated with a genetic cancer-predisposing syndrome.

Beckwith-Wiedemann Syndrome↗
PubMed1991

[Mechanism of parathyroid cell proliferation in primary hyperparathyroidism].

In primary hyperparathyroidism molecular biology techniques applied to the pathological parathyroid tissue have shown that cell proliferation is monoclonal in many sporadic adenomas and in the largest parathyroid glands of multiple endocrine neoplasia type 1 (MEN-1). On the other hand, monoclonality has not been found in sporadic hyperplasia and in the smaller parathyroid glands of MEN-1. In addition, abnormalities have been observed in chromosome 11 which contains the parathyroid hormone (PTH) gene and the MEN-1 associated gene. The PTH gene was rearranged in sporadic adenomas, and there was a varying degree of chromosome 11 allele delection in sporadic adenomas and in MEN-1. The relationship between these abnormalities and parathyroid cell proliferation is controverted, and further studies are required to determine their exact role in the development of primary hyperparathyroidism.

Cell Division↗