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Androgenetic alopecia is the most common form of hair loss, and baldness is often termed as a polygenic condition, but only a few of the genes are known. Ahmad and colleagues have studied alopecia universalis, a recessively inherited, comprehensive form of baldness, which has been seen in a six-generation Pakistani family. They cloned the human homologue of the hairless mouse gene, discovering that the affected people all harboured two mutated copies of the gene.

The genes involved in many genetic disorders have been identified using a technique known as chromosomal mapping. This technique uses chromosomal segments, known as markers, to isolate and identify the chromosomal regions between these markers. The genes involved in disorders such as Kallmann's syndrome, fragile X syndrome, colorectal cancer, early-onset familial Alzheimer's disease, and Marfan syndrome have all been identified. The latest discovery is that a defect in the gene for rhodopsin (a pigmented compound in the retina of the eye) occurs in one quarter of the cases of autosomal dominant retinitis pigmentosa, a disease which leads to blindness. Other genes involved in autosomal dominant retinitis pigmentosa have also been identified. The gene involved in choroideremia, a disease where the retina of the eye is degenerated, has been located. This gene is also thought to be involved in one form of Usher syndrome, where there is blindness and loss of hearing. Another gene involved in another type of deafness has also been identified. Research has also shown that different changes in a particular gene may cause a different disease. For example, individuals with certain mutations in the gene involved in cystic fibrosis do not develop the symptoms of cystic fibrosis but rather develop congenital absence of the vas deferens (the tube which carries sperm from the testis to the urethra). Certain genetic changes in the gene involved in Duchenne and Becker muscular dystrophies can affect the heart muscle instead of skeleton muscle and result in disorders of the heart instead of muscular dystrophy. It is predicted that with the techniques available and with new techniques that are being developed, over 100 genes that are involved in various genetic disorders will be identified in the near future. (Consumer Summary produced by Reliance Medical Information, Inc.)

The gene that is defective in cystic fibrosis (CF) was identified in 1989. In the past year-and-one half, substantial progress has been made in the understanding of the abnormalities caused by the defective gene. However, after the Fourth Annual North American and 1990 International Cystic Fibrosis Conference in October 1990, scientists agree that more research is necessary before improved health care can be offered to patients with CF. Recent advances in research on CF were discussed at the meeting including: the correction of the defect which occurs in CF by giving the normal gene to CF cells that are grown in culture; greater understanding of the CF gene and how the protein that is encoded by it is produced in certain cells and not others; what controls the activation of the CF gene; and what cells in the body produce the protein product. Additional advances include: the identification of the CF gene in the mouse, allowing the mouse to be used as an animal model for experimentation; investigating how the protein molecule works and what portions of the protein are involved in particular functions; and identifying other mutations, or genetic changes, that occur in patients with CF. In 70 percent of the patients with CF, the gene is mutated in one particular area. But approximately 61 other mutations causing CF have been identified. Some of these are found in 2 to 5 percent of the patients with CF, but others are only found in one particular individual. It is hoped that patients with CF can be treated with gene therapy; the normal gene can be introduced into the lungs of patients. Although this is possible, the meeting showed that more research is necessary before gene therapy for patients with CF will be available. (Consumer Summary produced by Reliance Medical Information, Inc.)

Three different studies conducted on multiple cases of breast and ovarian cancer to find out signs of BRCA1 mutations reveal nearly 22 distinct mutations, including frameshift and missense mutations, which lead to premature truncation of gene product. C3HC4 zinc-finger domain close to the N terminus is the only identifiable domain in the BRCA1 protein, which indicates that this motif is functionally significant for the protein. Other studies have helped to prepare detailed genetic maps and provide more information on binding protein.

Defects in three fibroblast growth factor receptor (FGFR) genes lead to hereditary bone disorders. A missense mutation in the region encoding the transmembrane domain causes achondroplasia, while Crouzon syndrome results from mutations in the alternatively spliced exon of FGFR2 on chromosome 10. In Pfeiffer syndrome mutation occurs in the extracellular position of FGFR1. Mutations of a few other genes such as CAG and SCA5 are responsible for many congenital bone defects.

Examination of previous analyses of the impact of consanguinity on mortality shows that though consanguineous marriages eliminate rare lethal alleles, they result in the inheritance of fatal diseases, leading to death. Comparison of the mortality rates of children of consanguineous and non-consanguineous parents reveals the higher rate of hereditary diseases in the former than in the latter due to the acute effects of the lethal alleles in inducing diseases such as autosomal recessive muscular dystrophy.

Mapping and research of the region covering the hereditary breast cancer and ovarian cancer facilitated the cloning of the BRCA1 gene that is responsible for these diseases. This map contains over 130 clones, covers 3.5 megabases of genomic DNA and maps the two nearest DNA markers surrounding BRCA1 that are recombinant in vital breast cancer families. Physical mapping is also vital to clone genes that are responsible for hereditary nonpolyposis colon cancer and genes present in chromosomes affecting sexual development.

New cloning techniques and linkage analysis aim to decipher common and complex polygenic diseases that involve several genetic loci contributing to the disease. Measures to inhibit complex disorder progress in humans aim to raise polymorphic, microsatellite pointer numbers for linkage analysis. Scientists are calculating the number of genes present in a genome to recognize the disease-causing genes.

Environmental and genetic factors contribute to atopic allergies, causing common fever, eczema and food allergies. Allergens such as pollens or house dust mites bind to IgE receptor in the serum of mast cells and cause the release of histamine-like inflammatory substances, resulting in sneezing, wheezing or coughing. A gene encoding beta subunit of FCepsilonRI is associated with 60% of atopy cases and the inheritance of atopy occurs through the maternal line. Delta F508, a primary mutation factor of the gene for cystic fibrosis, is another possible source.

Mysterious sequences occupy 97% of the human genome which comprises vast lengths of repetitive DNA connecting the genes and numerous intron sequences that punctuate the coding regions of the genes. A comparison of DNA sequences of different species reveals limited contiguous genomic DNA sequence and the genes show a high degree of conservation of the order of 75%. A survey of the entire region including 94% non-coding DNA produces a 71% similarity between mice and humans. The degree of sequence conservation is due to chromosomes which serve as 'information organelles' for storage, copying and evolution of information.

The characteristics of human genes are revealed by analyzing complementary DNA sequences. In the brain, there is an abundance of structural and regulatory proteins, while there is a predominance of polypeptides and secreted proteins in the liver. The directionally-cloned brain cDNA optimized the amount of coding information obtained from an expressed sequence tag (EST). EST accelerates the pace of gene discovery, and also predicts the scope for future research. EST helps in homology researches on nucleotides and proteins.

Insulin-dependent diabetes mellitus (IDDM) is caused by a complex interaction of genetic and environmental factors that conspire to induce autoimmune destruction of pancreatic B-cells. The genetic factors include the insulin gene in chromosome 11 and the HLA region in chromosome 6. Within this region, the class II genes, especially certain alleles of the DQ and DR loci, have been implicated in susceptibility to IDDM. Detailed analysis of these loci has identified residue 57 of DQB1 as important in conferring resistance to IDDM.

Research on the phenotype or genetic basis for retinal degeneration is the subject of three articles in the Mar 1993 issue of Nature Genetics. These phenotypes are linked to mutations that affect peripherin, a retinal protein, and with the loss of photoreceptors that characterizes retinitis pigmentosa (RP). B.E. Nichols and colleagues report a mutation associated with butterfly dystrophy. J. Wells and colleagues and K. Kajiwara and colleagues identify different phenotypes as causes of macular degeneration and RP.

A listing exists of 321 mapped locations of human genes with homologues for the cat, mouse and cow. The genes have been cloned and their locations on the chromosomes are given, providing a foundation for any further mapping studies. Stephen O'Brien and colleagues have produced the master map, and it will facilitate cross species studies since it represents mammalian orders of carnivores, primates, rodents and artiodactyls.

The gene responsible for Menkes disease has been described by three independent research groups. Deletion or abnormality of the gene interferes with proper cell metabolism of copper which in turn results in the degenerative brain disease. Copper ions are vital cofactors for many enzymes and their deficiency explains the majority of the disease's symptoms. The cloning of the Menkes gene suggests lines of inquiry for other X-linked diseases.

Gene therapy has focused in the past on ex vivo studies for rare diseases, but approval of three proposals for in vivo studies of cystic fibrosis by the Recombinant DNA Advisory Committee of the National Institutes of Health may change this. Gene therapy is having mixed results in at least 15 trials nationwide. European researchers may gain ground on American researchers in 1993. Dutch and Italian investigators are attempting to target stem cells to prolong treatment for genetic disease resulting in adenine deaminase deficiency.

Three papers published in the Dec 1992 issue of Nature Genetics reveal new findings about the genetic origin of Prader-Willi syndrome (PWS). PWS, which results from either the lack of a paternal gene or from having two copies of the maternal chromosome 15, causes obesity and developmental problems. Stuart Leff and colleagues report the association of the gene SNRPN with PWS, while Neal Copeland and Nancy Jenkins achieved a similar result. Bruce Cattanach and coworkers corroborated this finding by devising a mouse model of PWS.

Applying what is known about the mutation rates of bacterial populations to the forecasting of prevalence of human genetic disorders is the subject of an important article by J. Hastbacka and coworkers in the Nov 1992 Nature Genetics. The authors derive their approach from the 1943 research of Salavador Luria and Max Delbruck on the spontaneous occurrence of bacterial mutation. Hastbacka and colleagues have analysed the rates of genetic disorders in Finland and conclude that inherited human conditions such as diastrophic dysplasia may also arise unpredictably.

Identification of the mutations underlying nephrogenic diabetes insipidus (NDI) made significant progress as indicated by two articles in the Oct 1992 Nature Genetics announcing that two research groups have discovered nine new mutations linked to NDI. The defect that causes NDI, an X-linked recessive disorder, is thought to be located located in the vasopressin V2 receptor. Bernard van Oost and colleagues found three V2 receptor mutations while Jane Gitschier and colleagues found six mutations.

The problems bedeviling the development of mouse models for genetic disorders are discussed in two articles in the Sep 1992 Nature Genetics. Karen Steel and Richard Smith report the failure to breed a mouse model of the autosomal dominant condition Waardenburg's syndrome that would mirror the ear defects and deafness that are the chief human consequences of this disorder. T. Jordan and colleagues examine a similar failure to devise a mouse model for human aniridia. Learning why these disorders affect mice so differently from how they affect humans may increase knowledge of genetic variation.

Adenoviruses and herpesviruses may be useful alternatives to retroviruses for delivering therapeutic genes to diseased organs. These latest advances in gene therapy are reported in the Aug, 1992 issue of the journal Nature Genetics. Ron Crystal and colleagues report that adenoviruses transferred the lacZ gene and the human alpha-1-AT gene; this technique may aid in treating hemophilia and metabolic disorders. In addition, J.H. Wolfe and colleagues used herpesviruses to correct an abnormality in the beta-glucuronidase gene that is responsible for a type of mental retardation called Sly disease.

The use of genetic screening to locate carriers of the cystic fibrosis (CF) gene moved closer to reality when a two-year study of the Celtic people of western Brittany in France found 98% of all CF mutations. Claude Ferec and colleagues used a form of genetic screening called denaturing gradient gel electrophoresis to test for the CF transmembrane regulator gene that causes this severe form of lung disease. However, whether this testing method will succeed in a less homogeneous population is uncertain. Moreover, counselling and education will be essential to any screening program for CF.

In mid-September 1990, Congressman John Conyers of Michigan introduced a bill which would protect the individual's right to privacy about his or her own genetic information. Much of the concern stems from the possibility that detection of an abnormality on a genetic test might result in discrimination against the individual. Such discrimination has already occurred in some cases. People carrying a single copy of the sickle-cell anemia gene have been refused employment based on the mistaken belief that they are susceptible to the disease. Similar discrimination has occurred against individuals carrying the gene for Gaucher disease, a disorder of lipid metabolism. There is a very real concern that the public, and the people who are making employment decisions, are not able to properly evaluate genetic information. Persons without medical training may fail to realize that some genetic defects are not particularly severe, and that if an individual has such an abnormality it has no real relevance to decisions about employment, insurance, or adoption. Debate on the bill introduced by Conyers will begin in the Spring of 1991. (Consumer Summary produced by Reliance Medical Information, Inc.)