Non-insulin dependent diabetes mellitus (NIDDM) affects more than 100 million people worldwide and is associated with severe metabolic defects, including peripheral insulin resistance, elevated hepatic glucose production, and inappropriate insulin secretion. Family studies point to a major genetic component, but specific susceptibility genes have not yet been identified-except for rare early-onset forms with monogenic or mitochondrial inheritance. We have screened over 4,000 individuals from a population isolate in western Finland, identified 26 families (comprising 217 individuals) enriched for NIDDM and performed a genome-wide scan using non-parametric linkage analysis. We found no significant evidence for linkage when the families were analysed together, but strong evidence for linkage when families were classified according to mean insulin levels in affecteds (in oral glucose tolerance tests). Specifically, families with the lowest insulin levels showed linkage (P = 2 x 10(-6)) to chromosome 12 near D12S1349. Interestingly, this region contains the gene causing the rare, dominant, early-onset form of diabetes MODY3. Unlike MODY3 families, the Finnish families with low insulin have an age-of-onset typical for NIDDM (mean = 58 years). We infer the existence of a gene NIDDM2 causing NIDDM associated with low insulin secretion, and suggest that NIDDM2 and MODY3 may represent different alleles of the same gene.

Genome-wide nonparametric linkage analysis of 480 sib-pairs affected with type 2 diabetes revealed linkage to a previously unreported susceptibility locus on chromosome 18p11. This result improved with stringent subphenotyping using age-and sex-adjusted BMI, ultimately reaching a logarithm of odds of 3.82 (allele sharing 0.6654) at a point between markers D18S976 and D18S391 when the most obese 20% of the sample was analyzed. Several genes on chromosome 18 have been suggested as metabolic disease candidates, but none of these colocalize with our linkage result. We conclude that our results provide support for the presence of a currently uncharacterized gene on chromosome 18p, certain alleles of which confer increased susceptibility to type 2 diabetes in conjunction with obesity. We additionally observed moderate evidence for linkage to chromosome 1, near marker D1S3462; chromosome 4, near marker D4S2361; chromosome 5, near marker D5S1505; and chromosome 17, near marker D17S1301. Diabetes 50:675-680, 2001

Carboxypeptidase E (CPE) is involved in the biosynthesis of peptide hormones and neurotransmitters, including insulin. One of the features of type 2 diabetes mellitus (T2DM) is an elevation in the proinsulin level and/or proinsulin/insulin molar ratio, suggesting that mutations in proinsulin processing enzymes may contribute to the development of T2DM. We scanned CPE for mutations in a collection of Ashkenazi T2DM families and identified five novel single nucleotide polymorphisms (SNPs). An SNP in the 283(rd) codon, c.847C>T, changes arginine to tryptophan (R283W). The residue Arg283 is conserved among CPE orthologs as well as most enzymatically active metallocarboxypeptidases. Of the 272 Ashkenazi T2DM pedigrees screened, we found four families segregating R283W. Within these four families, patients who inherited one copy of this variant had much earlier age of onset for T2DM. The R283W CPE protein cleaves peptide substrates with substantially lower efficiencies and is less stable at elevated temperature. In addition, the R283W CPE variant has a narrower pH optimum and is much less active at pH 6.0-6.5, indicating that the R283W CPE variant would be substantially less active than wild type CPE in the trans-Golgi network and immature secretory vesicles where the enzyme functions in vivo. To summarize, we uncovered a rare non-conservative missense mutation in CPE and demonstrated that the mutant protein has altered enzymatic properties. We predict that this mutant could cause hyperproinsulinism and diabetes in the homozygous state.

Psychosocial Genetic Counseling by Jon Weil was written to fill a niche in the literature. It is one of the only books to deal with the counseling aspects of genetic counseling; it does so with more depth and breadth than any other book currently available. Its target audience is genetic counseling students and practicing genetic counselors. Other health providers who find themselves needing to know more about genetic counseling such as medical geneticists, nurses, social workers, psychologists, and so on would also benefit from reading this text. Practical advice is combined with theory primarily through the use of vignettes and sample dialog. This is a highly effective presentation and is one of the major strengths of the book. The fact that it is very specific will make it very valuable to the target audience, but may decrease its wider appeal. For genetic counselors it is uniquely useful-there are many books on counseling in general, but very few that provide what this book provides.The author, Jon Weil, is especially well qualified to write such a book. The director of the Berkeley Genetic Counseling Program (University of California, Berkeley) for many years, he has a PhD in both Social-Clinical Psychology and Genetics. In his private psychotherapy practice, he has a special interest in genetic diseases and birth defects. His years of experience are reflected in the practical and elegantly worded guidance that he provides throughout the text. One reader commented, "I particularly liked those scenarios that contrasted some of the more common mistakes and less effective responses with more effective alternatives."Since genetic counseling students will comprise a main audience for this book, a group of 11 from the Brandeis Genetic Counseling Program (10 students, 1 faculty member) set out to create this review. Each read and commented on a chapter/section in which she had a particular interest or expertise. Then one of us (KSK) compiled this summary.The book is intended to be read at three levels and that is one of its strengths. On the first level, the book exposes the counselor to many of the most common counseling situations faced in genetic counseling: counseling individuals as part of a family, counseling couples, working with children, working with individuals of various cultural backgrounds to name a few. It lays out the major issues and counseling strategies for each of these areas. Upon closer reading, the counselor can