This book is one of our contemporary medical bibles. It needs no introduction; those who have frequent need of it know it very well, and those who use it less often seek it out on the library shelf when problems arise. The book is truly encyclopedic. Everything relevant discovered during the six-year intervals between publication finds its way into these pages. By today's standards, its 1,778 closely packed small-print pages are a bargain. The mutant gene is both hero and villain in this book. It is reponsible for the biochemical abnormality that results in disease, no matter how rare a given abnormality may be. By the same token, however, it is truly an experiment of nature, shedding light on fundamental metabolic sequences and biologic mechanisms. This volume, more than most, explains the contributions of the laboratory to clinical medicine. Each chapter seems to have been rewritten, so that the exciting

The Metabolic Basis Of Inherited Disease.

https://www.cell.com/cell/pdf/0092-8674(93)90279-Y.pdf

Circular transcripts of the testis-determining gene Sry in adult mouse testis

The pivotal point of vertebrate sex determination is the development of the gonad into a testis or ovary, which governs phenotypic sex through the production of hormones. The identification of Sry, the genetic switch that controls testis development in mammals, fuelled the race for the discovery of downstream pathways. Comparative analyses of XY versus XX gonadogenesis in both mouse and human genetic mutants have uncovered a burgeoning network of intra- and extra-cellular pathways. Here, we review the old and new players that are involved in the initial steps of testis and ovary development.

One tissue, two fates: molecular genetic events that underlie testis versus ovary development.

Chromosomally derived sterility has long been recognized. A review of the literature of somatic chromosome investigations in infertile males has shown that 13.7% of azoospermic males and 4.6% of oligozoospermic males have an abnormal karyotype. In the first group, sex chromosome abnormalities predominate (mainly 47,XXY), whereas in the latter, autosome anomalies (i.e. Robertsonian and reciprocal translocations) are the most frequent. A similar review on meiotic studies revealed that meiotic chromosome anomalies can explain male infertility in 4.3-40.4% of patients. Recently, fluorescent in-situ hybridization studies on spermatozoa from infertile men were published; it was suggested that both X-Y pairing and pairing of the autosomes were impaired, resulting in spermatogenic disruption. We investigated cytogenetically 694 infertile men with abnormal sperm parameters. More patients are needed for this research to investigate the relationship, if any, between the type of chromosome abnormality and its influence on the number, morphology and motility of spermatozoa. To be able to provide proper counselling for those couples whose male infertility can now be treated by intracytoplasmic sperm injection, it is suggested that clinical investigations should include mitotic and meiotic studies, an analysis of the chromosome content of individual spermatozoa and a DNA analysis of blood and spermatozoa to detect partially deleted Y chromosome material.

Cytogenetics of infertile men

Molecular basis of human 46X,Y sex reversal revealed from the three-dimensional solution structure of the human SRY-DNA complex.

XY females (n=17) were analysed for mutations in SRY (sex-determining region Y gene), a gene that has recently been equated with the testis determining factor (TDF). SRY sequences were amplified by the polymerase chain reaction (PCR) and analysed by both the single strand conformational polymorphism assay (SSCP) and DNA sequencing. The DNA from two individuals gave altered SSCP patterns; only these two individuals showed any DNA sequence variation. In both cases, a single base change was found, one altering a tryptophan codon to a stop codon, the other causing a glycine to arginine amino acid substitution. These substitutions lie in the high mobility group (HMG)-related box of the SRY protein, a potential DNA-binding domain. The corresponding regions of DNA from the father of one individual and the paternal uncle of the other, were sequenced and found to be normal. Thus, in both cases, sex reversal is associated with de novo mutations in SRY. Combining this data with two previously published reports, a total of 40 XY females have now been analysed for mutations in SRY. The number of de novo mutations in SRY is now doubled to four, adding further strength to the argument that SRY is TDF.

Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal

XX maleness is the most common condition in which testes develop in the absence of a cytogenetically detectable Y chromosome. Using molecular techniques, it is possible to detect Yp sequences in the majority of XX males. In this study, we could detect Y-specific sequences, including the sex-determining region of the Y chromosome (SRY), using fluorescence in situ hybridization. In 5 out of 6 previously unpublished XX males, SRY was translocated onto the terminal part of an X chromosome. This is the first report in which translocation of an SRY-bearing fragment to an X chromosome in XX males could be directly demonstrated.

Molecular cytogenetic analysis of XX males using Y-specific DNA sequences, including SRY.

• We present a large kindred that contained patients with either adrenoleukodystrophy (ALD) or adrenomyeloneuropathy (AMN). The pedigree clearly supported the X-linked mode of inheritance of the nonneonatal form of ALD/AMN. Analysis with DNA markers at Xq28 suggested segregation of both ALD and AMN with an identical haplotype. This indicated that nonneonatal ALD and AMN are caused by a mutation in the same gene at Xq28. It showed, furthermore, that phenotypic differences between ALD and AMN are not necessarily the consequence of allelic heterogeneity due to different mutations within the same gene. The maximal lod score for linkage of the ALD/AMN gene and the multiallelic anonymous DNA marker at DXS52 was 3.0 at a recombination fraction of 0.00. This made a prenatal or presymptomatic diagnosis and heterozygote detection by DNA analysis with this marker reliable.

Linkage of DNA markers at Xq28 to adrenoleukodystrophy and adrenomyeloneuropathy present within the same family.

The association of astrocytoma and pituitary adenoma in a patient with alcaptonuria

Cloning and sequencing of the CF gene has identified a three-base-pair deletion (delta F508) responsible for CF in the majority of CF patients (Kerem et al. 1989). We have used the polymerase chain reaction with oligonucleotide primers bridging the delta F508 deletion to analyze the presence or absence of this mutation in the Belgian CF population. The delta F508 mutation was present in 80% (57 on 71) of CF chromosomes from 36 unrelated Belgian CF families from the region of Antwerp. This mutation was associated with haplotype B for the KM.19-XV-2c RFLPs as 93% (53 on 57) of the CF chromosomes with the delta F508 mutation carried haplotype B.

B. Van der Auwera

Papers

Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal

Molecular cytogenetic analysis of XX males using Y-specific DNA sequences, including SRY.

Linkage of DNA markers at Xq28 to adrenoleukodystrophy and adrenomyeloneuropathy present within the same family.

The association of astrocytoma and pituitary adenoma in a patient with alcaptonuria

Frequency of the phenylalanine deletion (delta F508) in the CF gene of Belgian cystic fibrosis patients.