Biomedical subjects
Publications and source records attributed to M Jeanpierre.
We present the results of an international collaborative study aimed at estimating the ratio of male to female mutation rates in Duchenne muscular dystrophy based on the method of C. Müller and T. Grimm. With a sample size of 295, this ratio is found to be very close to 1, thus giving evidence for equal mutation rates in males and females in Duchenne muscular dystrophy.
The likelihood of a genotype of an unsampled individual depends upon genetic data from relatives. When these relatives may be carriers of a mutation as in X-linked disease, the likelihood of a genotype is altered by the consequences of the possible genotypes on offspring. The probabilities of the possible genotypes are easily derived from the probabilities conditional on the genotype obtained from a computer program aimed at risk calculation. This procedure of genotype reconstruction brings to light a potential hazard in the interpretation of computer data: a compound risk may be better represented as the harmonic mean of a set of conditional probabilities than the simple average of these probabilities.
Germinal mosaicism is a major problem in risk estimation for an X-linked disease. A mutation can happen anytime in germ cell development, and the proportion of germ cells bearing the mutated gene is twice the probability of recurrence of the mutation. This proportion could be either very low in late mutations or very high in germinal and somatic mosaicism. When this heterogeneity is taken into consideration, the distribution of the recurrence risk is conveniently represented as a set of discrete classes that may be derived either from models of gametogenesis or from empirical data. A computer program taking into account germinal mosaicism has been devised to calculate the probability of a possible carrier belonging to any of these classes, in order to settle the origin of the mutation of a given family. Germinal mosaicism increases the probability of inheriting the mutation, but this effect is always lowered by the possibility of heterogeneity. When the mother of a possible carrier is not herself a carrier, the risk of her daughter being a carrier is approximately halved, even under the assumption of a high recurrence risk from mosaicism.
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X linked retinoschisis (RS) is a vitreoretinal disease resulting from microcystic degeneration of the macula associated with peripheral lesions. The disease gene has already been assigned to the distal short arm of the X chromosome (Xp22.2) by linkage studies. In order to contribute both to a better localisation of the RS locus and to genetic counselling in RS families, we have carried out a clinical and genetic analysis in seven pedigrees. We show, first, that in contrast with previous reports, heterozygote carriers frequently express the disease, and display peripheral retinal alterations similar to those found in affected males. Second, while distal markers DXS16, DXS207, and DXS43 are closely linked to the disease locus, a high level of recombination events was found with centromeric markers, namely DXS274, DXS41, and DXS164. These findings must be taken into account for both carrier detection and prenatal diagnosis in X linked RS.
The computation of genetic risk in the highly endogamous family of an ancient greek god and goddess has been published in this journal as a pleasant puzzle (Ropartz, 1985 and appendix 1). This calculation was assumed to be direct and straightforward. However, a Bayesian computation taking in account most of the available information of the risk is possible. Four solutions of this quiz are given. These solutions illustrate the different strategies which can be followed when facing actual genetic problems.
To define more precisely, in molecular terms, the region involved in Beckwith-Wiedemann syndrome (BWS), we have studied patients with BWS and a constitutional duplication of 11p15 using eight 11p15 markers. In the first case with a de novo duplication and extra material on 11p, the region spanning pter to CALCA, excluded, was duplicated. In the second case, the rearrangement was characterized using somatic cell hybrids established with lymphocytes from the father who carried a balanced translocation t(11;18)(p15.4;p11.1). The breakpoint lay exactly in the same region. It could thus be inferred that the two sons, who were the first cases reported of BWS with dup11p15 and adrenocortical carcinoma (ADCC), carried a duplication similar to that observed in the first case. Together with evidence for specific somatic chromosomal events leading to loss of 11p15 alleles in familial cases of ADCC, it can be hypothesized that a gene involved in predisposition to ADCC maps to region 11p15.5.
A biotinylated probe (L23-21) specific for the 1q12 band of human karyotype was used to detect the 1q segment in interphase nuclei of breast and colon carcinomas. This probe was selected because trisomy or polysomy 1q is the most frequent chromosomal change observed in solid tumors. This method enables cancerous cells, including near-diploid ones carrying an unbalanced rearrangement of 1q, to be easily identified.
Calculation of carrier risk of an X linked disease may be performed on a small computer after DNA analysis, but a method for rapid hand estimation of the risk is still useful for a quick check of the results and weighing the relative importance of each element of information, such as the determination of a haplotype. Each risk estimation is a function of a prior risk and the product of likelihood ratios and these terms are derived themselves from parameters such as fitness or the relative mutation rate in male and female gametes. Even if it is often difficult to have strong experimental estimation of these variables, the existence of a normal father or grandfather must be considered whenever male fitness is not null. The likelihood ratio for a woman for not being a carrier, when her father is not affected and her mother has herself a likelihood R for not having the mutated gene, may be expressed as the ratio 2R/(CmR + 1), with Cm being a function of male fitness and relative mutation rate. Cm represents the odds ratio for the mother of a carrier not to be a carrier, given that the father of the known carrier is not affected. This formula can be used recurrently and reduces to 2R/(R + 1) in lethal X linked disease. When likelihood ratios are expressed as an algebraic function, maximum values are easily determined, hence fixing the limits of DNA analysis.
A few cases of Beckwith-Wiedemann syndrome (BWS) have in common a duplication of 11p15. Among the genes located in 11p15, c-Ha-ras 1 (HRAS1), insulin (INS), and insulin-like growth factor II (IGF2) may account for the clinical features and the increased risk for malignancy. Using eight 11p15 markers including HRAS1, INS and IGF2 we have studied eight sporadic and hereditary cases of BWS whether or not associated with a nephroblastoma. By gene dosage determination and family studies, we have shown the following: the eight patients examined had an apparent diploid representation of all of the eight markers studied, thus indicating that a microduplication of these markers or of the region characterized by these markers is not a common event in BWS; in a family with three affected sibs the genes for HRAS1 and INS/IGF2 did not cosegregate with BWS and therefore may not participate in the pathogenic processes here observed.
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The coming of molecular biology has greatly modified the concept of genetic counselling and prenatal diagnosis of Duchenne muscular dystrophy. The most important stages of the genetic counselling are reported: estimate of the risk and carrier detection. This heterozygote detection is now possible in a few cases owing to polymorphic DNA markers recently identified that are genetically linked to the DMD gene locus and detected with probes. An analysis of foetal DNA is also possible and allows us to consider prenatal diagnosis of this affection. This study is yet limited by two impediments: on one hand low rate of informative families, on the other hand use of markers that are not very closely linked to DMD involving recombinations and risks of errors. The solution of these problems is in the use of linked DNA markers with the best polymorphism flanking the Duchenne muscular dystrophy locus. Finally the authors report the necessity of strict collaboration systems between clinical experts, geneticists, biologists and informaticians.
The estimation of genetic risks in X-linked recessive disorders is a special case of Bayesian approach to probability calculation. Computing directly an estimation of the inverse of the risk is easier in this particular situation of only two mutually exclusive hypothesis: this function can be written in the form T = 1 + (To -1) X R, where R is a product of likehood ratios. The ratio of two probability density function represent a single factor, which is more manipulatable than the two components of the classical method.
The single X chromosome of a girl with Turner syndrome (45,X) and typical Duchenne muscular dystrophy was investigated at the chromosomal and DNA levels. No visible abnormality of the residual X chromosome was found upon high-resolution R-banding. The DNA was analysed by Southern blotting and hybridization with seven cloned probes mapping in the Xp21 region where the Duchenne locus is thought to be located. A molecular deletion was detected with probes pERT 87.1, pERT 87.8, and pERT 87.15. The other probes (754, C7, 99.6, and RC8) gave a normal signal. The DNA alleles seen in the two parents indicated that the deletion found in the propositus had occurred de novo on a maternal X chromosome.
Several clones containing clusters of repetitive elements were isolated from a human chromosome 22 specific library. An EcoRI-XhoI fragment of 860bp was subcloned and was shown to belong to a family of tandemly repeated DNA linked to the Y-specific 3.4 kb HaeIII band. This probe hybridizes to several sets of sequences or subfamilies. The most abundant subfamily is a 1.8kb long sequence containing one EcoRV site, and in most repeats, one AvaII and one KpnI site. Using human-rodent somatic cell hybrid DNA, we have shown that this cluster is present on human chromosome 9 although presence on chromosome 15 is not excluded. Another subfamily, 6.1kb long, appears to be exclusive of chromosome 16. By in situ hybridization with metaphasic chromosomes, these sets of repeats were mapped to the constitutive heterochromatin of a few chromosomes. Coexistence in one genome of long tandem repeats of distinct organization but similar length may represent the outcome of a continuous process of fixation of variant sequences. Homologous repeats are also abundant in four higher primate genomes (Orangutan, gorilla, chimpanzee, and man) but absent in other primates (African green monkey, rhesus monkey, baboon, and mouse lemur).
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Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder for which the biochemical defect is as yet unknown. Recently, two cloned segments of human X-chromosome DNA have been described which detect structural alterations within or near the genetic locus responsible for the disorder. Both of these cloned segments were described as tightly linked to the locus and were capable of detecting deletions in the DNA of boys affected with DMD. In an attempt to determine more precisely the occurrence of these deletions within a large population of DMD patients and the accuracy of one of the segments, DXS164 (pERT87), in determining the inheritance of the DMD X chromosome, the subclones 1, 8 and 15 were made available to many investigators throughout the world. Here we describe the combined results of more than 20 research laboratories with respect to the occurrence of deletions at the DXS164 locus in DNA samples isolated from patients with DMD and Becker muscular dystrophy (BMD). The results indicate that the DXS164 locus apparently recombines with DMD 5% of the time, but is probably located between independent sites of mutation which yield DMD. The breakpoints of some deletions are delineated within the DXS164 locus, and it is evident that the deletions at the DMD locus are frequent and extremely large.