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M Leppert

Publications and source records attributed to M Leppert.

At least 127 records · Page 7Linked to original sources
PubMed1990

Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3.

SPINAL muscular atrophy (SMA) describes a group of heritable degenerative diseases that selectively affect the alpha-motor neuron. Childhood-onset SMAs rank second in frequency to cystic fibrosis among autosomal recessive disorders, and are the leading cause of heritable infant mortality. Predictions that genetic heterogeneity underlies the differences between types of SMA, together with the aggressive nature of the most-severe infantile form, make linkage analysis of SMA potentially complex. We have now analysed 13 clinically heterogeneous SMA families. We find that 'chronic' childhood-onset SMA (including intermediate SMA or SMA type II, and Kugelberg-Welander or SMA type III) is genetically homogeneous, mapping to chromosomal region 5q11.2-13.3.

Adolescent↗
PubMed1990

Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps.

We studied a large kindred with a history of colorectal cancer of early onset. Proctosigmoidoscopic examination of 51 family members identified only 2 with familial polyposis coli, which strongly predisposes those who have it to colorectal cancer and which is defined as the presence of more than 100 polyps in the colon. However, eight family members had 2 to 40 colonic polyps. We suspected that in this family, colorectal cancer was the result of a mutation in the gene on chromosome 5 that is responsible for familial polyposis coli. To test our hypothesis, we obtained genotypic information on 81 family members with respect to seven polymorphic DNA markers previously shown to be linked to the locus for familial polyposis coli. Multilocus analysis of the data demonstrated genetic linkage (lod score, 5.58) between these markers and the locus responsible for the defined syndrome of colonic polyps or colorectal cancer in this kindred. These findings constitute evidence that the genetic defect in this family is a mutation in the gene that causes familial polyposis coli. We conclude that mutations at the genetic locus for familial polyposis coli may be the cause of other, more subtle syndromes involving an inherited susceptibility to colonic adenomatous polyps and colorectal cancer.

Adenomatous Polyposis Coli↗
PubMed1990

R-banding and nonisotopic in situ hybridization: precise localization of the human type II collagen gene (COL2A1).

A new mapping system, based on nonisotopic in situ hybridization combined with fluorescent staining of replicated prometaphase R-bands, is described. Replication of the bands is achieved by treatment of thymidine-synchronized cells with bromodeoxyuridine. The human COL2A1 gene was mapped to band 12q13.11-q13.12 in this manner, to illustrate the potential of the technique for improving the precision of chromosomal mapping and physical ordering of genes.

Chromosome Banding↗
PubMed1990

A detailed genetic map of the long arm of chromosome 11.

We describe 14 new restriction fragment length polymorphisms, corresponding to 13 loci on the long arm of chromosome 11. A detailed genetic map of chromosome 11q has been constructed from these and other loci (a total of 31 loci) typed in 59 reference families. The 23 most informative markers were selected to establish a map with a strongly supported order; regional localizations are provided for eight other markers. The loci span 88 cM in males and 148 cM in females and form a dense continuum on 11q. These ordered polymorphic markers will be of help in studying the genes responsible for several diseases that have been localized to this region, including genes responsible for multiple endocrine neoplasia type I (MEN1), ataxia telangiectasia (AT), tuberous sclerosis (TSC), and some forms of asthma and rhinitis.

Chromosome Mapping↗
PubMed1990

A primary map of 24 loci on human chromosome 16.

A primary genetic map of chromosome 16 has been constructed by linkage analysis of 24 polymorphic loci, typed in 59 reference families. These loci form a continuous map that covers the whole chromosome and spans genetic distances of 187 cM in males and 226 cM in females. Most of the sex-specific recombination rate difference comes from a nontelomeric region that covers 10 cM in males and 74 cM in females. Both telomeric regions show the opposite trend, with a significant increase in the male recombination rate.

Chromosome Fragility↗
PubMed1990

Mapping recessive ophthalmic diseases: linkage of the locus for Usher syndrome type II to a DNA marker on chromosome 1q.

Usher syndrome is a heterogeneous group of autosomal recessive disorders that combines variably severe congenital neurosensory hearing impairment with progressive night-blindness and visual loss similar to that in retinitis pigmentosa. Usher syndrome type I is distinguished by profound congenital (preverbal) deafness and retinal disease with onset in the first decade of life. Usher syndrome type II is characterized by partial hearing impairment and retinal dystrophy that occurs in late adolescence or early adulthood. The chromosomal assignment and the regional localization of the genetic mutation(s) causing the Usher syndromes are unknown. We analyzed a panel of polymorphic genomic markers for linkage to the disease gene among six families with Usher syndrome type I and 22 families with Usher syndrome type II. Significant linkage was established between Usher syndrome type II and the DNA marker locus THH33 (D1S81), which maps to chromosome 1q. The most likely location of the disease gene is at a map distance of 9 cM from THH33 (lod score 6.5). The same marker failed to show linkage in families segregating an allele for Usher syndrome type I. These data confirm the provisional assignment of the locus for Usher syndrome type II to the distal end of chromosome 1q and demonstrate that the clinical heterogeneity between Usher types I and II is caused by mutational events at different genetic loci. Regional localization has the potential to improve carrier detection and to provide antenatal diagnosis in families at risk for the disease.

Blotting, Southern↗
PubMed1990

Diagnosis of neurofibromatosis I by using tightly linked, flanking DNA markers.

We tested 132 individuals from 21 families segregating an allele for neurofibromatosis type 1 (NF-1), by using nine RFLPs tightly linked to the NF-1 locus. Family members had requested DNA testing either to determine whether "at risk" children were carrying the NF-1 allele or to determine whether their respective families would be informative for prenatal testing. Predictions about whether a child carries the NF-1 mutation were possible for all 32 at-risk offspring (greater than 98% accuracy based on the recombination estimates currently available for these DNA markers). At least one informative probe was available for all 23 matings in these 21 families; flanking markers were informative for 10 matings. Pairwise analysis showed that several of the polymorphisms were in tight linkage disequilibrium; few recombination events were observed with these markers in the families under study. We conclude that the DNA probes used in this study perform well for diagnostic testing of NF-1 in familial cases. A subset of five probe-enzyme systems (pHHH202/RsaI, p11-3C4.2/MspI, pTH17.19/Bg/II, p11-2C11.7/BamHI, and p11-2F9.8/TaqI) provide reliable linkage information for both clinical testing and prenatal diagnosis.

Alleles↗
PubMed1990

Genetic linkage and heterogeneity in type I Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy type I).

The segregation patterns of DNA markers from the pericentromeric regions of chromosomes 1 and 17 were studied in seven pedigrees segregating an autosomal dominant gene for Charcot-Marie-Tooth neuropathy type I (CMT I; hereditary motor and sensory neuropathy I). A multilocus analysis with four markers (pMCR-3, pMUC10, FY, and pMLAJ1) spanning the pericentromeric region of chromosome 1 excluded the CMT I gene from this region in six pedigrees but gave some evidence for linkage to the region of Duffy in one pedigree. Linkage of the CMT I gene to markers in the pericentromeric region of chromosome 17 (markers pA10-41, pEW301, p3.6, and pTH17.19) was established; however, in these seven pedigrees homogeneity analysis with chromosome 17 markers detected significant genetic heterogeneity. This analysis suggested that three of the seven pedigrees are not linked to this same region. Overall, two of the seven CMT I pedigrees were not linked to markers tested from chromosomes 1 or 17. These results confirm genetic heterogeneity in CMT I and implicate the existence of a third autosomal locus, in addition to a locus on chromosome 17, and a probable locus on chromosome 1. This evidence of etiological heterogeneity, supported by statistical tests, will have to be taken into consideration when fine-structure genetic maps of the regions around CMT I are constructed.

Charcot-Marie-Tooth Disease↗
PubMed1989

Clinical and pathological associations with allelic loss in colorectal carcinoma [corrected].

Clinical and pathological associations with molecular genetic alterations were studied in colorectal carcinomas from 83 patients. Fractional allelic loss, a measure of allelic deletions throughout the genome, and allelic deletions of specific chromosomal arms (the short arm of 17 and long arm of 18) each provided independent prognostic information by multivariate analysis when considered individually with Dukes' classification. Distant metastasis was significantly associated with high fractional allelic loss and with deletions of 17p and 18q. Mutations of ras proto-oncogenes and deletions of 5q had no prognostic importance. Statistically significant associations were also found between allelic losses and a family history of cancer, left-sided tumor location, and absence of extracellular tumor mucin. Allelic deletion analysis thus identified subsets of colorectal carcinoma with increased predilection for distant metastasis and cancer-related death. Further studies may define a subset of genetic alterations that can be used clinically to help assess prognosis.

Adult↗
PubMed1989

Benign familial neonatal convulsions linked to genetic markers on chromosome 20.

Recurrent seizures, commonly known as epilepsies, occur in 1.7% of the general population by age 40. The factors that initiate or underlie seizures are not well understood, but trauma, infectious disease and genetics have been implicated. An understanding of the molecular basis of seizures would shed light on the basic mechanisms of neuronal homeostasis and allow new therapeutic strategies to be explored. Here, we report the mapping of an epilepsy gene to a specific chromosomal region, on the basis of cosegregation of two closely-linked DNA markers with a form of epilepsy known as benign familial neonatal convulsions (BFNC2, 12120 in ref. 3). The linked markers confirm the genetic basis and autosomal dominant inheritance of this trait, and localize the gene causing BFNC in this family to the long arm of chromosome 20. This regional placement is the first step towards the isolation of a gene involved in neuronal activity in the human brain.

Chromosome Mapping↗
PubMed1989

Human type II collagen gene (COL2A1) assigned to chromosome 12q13.1-q13.2 by in situ hybridization with biotinylated DNA probe.

We have made a regional assignment of the type II collagen gene (COL2A1) on human chromosome 12 by means of an in situ hybridization technique with a biotinylated DNA probe. The precise localization of the signal was mapped to the band 12q13.1-q13.2. This result was in agreement with the previous mapping by isotopic in situ hybridization technique (12q13.1-q13.2), but not with the result of Southern hybridization analysis using somatic cell hybrids (12q14.3).

Chromosome Banding↗
PubMed1989

Twenty-five loci form a continuous linkage map of markers for human chromosome 7.

We have constructed a primary genetic linkage map from DNA markers that define 25 loci on chromosome 7. The markers form a continuous linkage group of 141 cM in males and 340 cM in females; female genetic distances were on average more than twofold higher than those in males throughout the chromosome. The average heterozygosity of the loci was 45%. A subset of the markers can be used for efficient application of this map to studies of human genetic disease.

Alleles↗
PubMed1989

Characterization of eight VNTR loci by agarose gel electrophoresis.

Allelic frequencies and their confidence intervals were obtained for eight independent VNTR loci from a sample of more than 75 Utah Caucasians. Using high-resolution agarose gel electrophoresis, we were able to resolve alleles at the D17S5 locus that differed by only one repeating unit; it was therefore possible to name the alleles according to the number of repeating units each contained. Two a priori probabilities were calculated for each VNTR locus separately and for all eight loci jointly: (i) the "power of exclusion" for an alleged father/mother/child trio and for an alleged parent/child duo, and (ii) the "probability of matching" when two unrelated individuals or two siblings are genotyped.

Alleles↗
PubMed1989

A genetic linkage map of markers for human chromosome 20.

A continuous genetic linkage map with five polymorphic DNA markers, including one that defines a locus containing a variable number of tandem repeats (VNTR), has been constructed from genotypic analysis of 59 large reference families. The map spans a genetic distance of 105 cM in males and 115 cM in females and provides initial anchor points for a high-resolution map of human chromosome 20.

Alleles↗
PubMed1989

Frequent recombination is observed in the distal end of the long arm of chromosome 14.

We have constructed a high-resolution map of the distal region (q32) of the long arm of human chromosome 14, with 11 loci including 6 variable number of tandem repeat markers. The map covers 66 cM in males and 53 cM in females. The recombination frequency in this region is more than five times that expected in a region of this physical size, and in our data set the frequency in males was higher than that in females at some intervals. This unusually high density of crossingover occurs in a part of chromosome 14 where translocations are frequently observed in somatic cells.

Chromosome Mapping↗