An understanding of the basic defect in the inherited disorder cystic fibrosis requires cloning of the cystic fibrosis gene and definition of its protein product. In the absence of direct functional information, chromosomal map position is a guide for locating the gene. Chromosome walking and jumping and complementary DNA hybridization were used to isolate DNA sequences, encompassing more than 500,000 base pairs, from the cystic fibrosis region on the long arm of human chromosome 7. Several transcribed sequences and conserved segments were identified in this cloned region. One of these corresponds to the cystic fibrosis gene and spans approximately 250,000 base pairs of genomic DNA.

Identification of the cystic fibrosis gene: Chromosome walking and jumping

Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17

There has always been great interest in animal models of human genetic disease, and mice provide the largest number of examples. A mutation in the homologous gene in mice does not always lead to the same phenotype as is found in man, however. Recent studies made it apparent that one mutation can have markedly different phenotypes when placed on different genetic backgrounds. This variation is due to different alleles at modifying loci in various inbred strains. Thus, if one wishes to obtain the optimal mouse model for a human disease, one needs to choose the correct genetic background as well as the correct mutation.

Mouse models of human genetic disease: which mouse is more like a man?

Familial cancer syndromes reflect an inherited predisposition to develop benign and malignant tumors. Clinically, the cancers occur at an earlier age and involve multiple foci of tumor formation at multiple sites. In the past 10 years, the molecular basis of many of these cancer syndromes have been unraveled with the advent of powerful genetic technologies. Entities which were hypothesized to be related on the basis of clinical features have now been shown to be linked or disparate through genetic analysis. This article reviews some of the recent advances in the clinical and molecular aspects of familial cancer syndromes that involve the skin. (J Am Acad Dermatol 2000;42:939–69.) Learning Objective: After completing this article, the reader should become (1) fluent with some basic genetic principles underlying the mechanisms of cancer predisposition and positional cloning and (2) aware of the recent breakthroughs in the identification of familial cancer syndrome disease genes.

https://www.jaad.org/article/S0190-9622(00)90285-8/pdf

Update on familial cancer syndromes and the skin

Marfan syndrome is an autosomal dominant disease of connective tissue caused by mutations in the fibrillin-1 encoding gene FBN1. Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within and between families. Here we describe a new mouse model of MFS that recapitulates the clinical heterogeneity of the syndrome in humans. Heterozygotes for the mutant Fbn1 allele mgΔloxPneo, carrying the same internal deletion of exons 19–24 as the mgΔ mouse model, present defective microfibrillar deposition, emphysema, deterioration of aortic wall and kyphosis. However, the onset of a clinical phenotypes is earlier in the 129/Sv than in C57BL/6 background, indicating the existence of genetic modifiers of MFS between these two mouse strains. In addition, we characterized a wide clinical variability within the 129/Sv congenic heterozygotes, suggesting involvement of epigenetic factors in disease severity. Finally, we show a strong negative correlation between overall levels of Fbn1 expression and the severity of the phenotypes, corroborating the suggested protective role of normal fibrillin-1 in MFS pathogenesis, and supporting the development of therapies based on increasing Fbn1 expression.

A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression.

Linkage analysis of von Recklinghausen neurofibromatosis to DNA markers on chromosome 17

A potential animal model for studying CF heterozygote advantage: genetic variation in theophylline-inducible colonic chloride currents among inbred strains of mice.

Ann M. Sweet

Papers

Linkage analysis of von Recklinghausen neurofibromatosis to DNA markers on chromosome 17

A potential animal model for studying CF heterozygote advantage: genetic variation in theophylline-inducible colonic chloride currents among inbred strains of mice.

An EcoRI polymorphism for pMet G in inbred mice.