Nature Genetics pp 218 - 221 and pp 131 - 132

Up to 800,000 people in the United States are estimated to have type 1 diabetes (T1D), a disease involving the destruction of the insulin-producing cells of the pancreas and influenced by complex environmental and genetic factors. Until now, only the histocompatibility genes—which influence immune response—have been implicated in T1D. Grant Morahan and colleagues (of the Walter and Eliza Hall Institute for Medical Research in Melbourne, Australia) have now found that individuals who have specific variants of the gene encoding one component of interleukin 12 (IL-12) have a higher risk of developing T1D.

IL-12 is a cytokine; as such, it mediates the signals that the different cells of the immune system send to each other during response to infection. When injected in an animal model of T1D, the non-obese diabetic (NOD) mouse, IL-12 activates a specific cell type, the Th1 class of helper T lymphocytes. In an 'autoimmune' reaction, these cells orchestrate the destruction of the insulin-producing pancreatic beta-?cells, which is the hallmark of type 1 diabetes. Previous searches for genes predisposing to T1D had failed to detect the contribution of IL-12. Inspired by the NOD mouse model, Grant Morahan and colleagues applied more refined statistical 'filters' and discovered the association between some variants of the gene encoding one subunit of IL-12 and T1D. They also observed that the gene variants that confer risk drive a higher rate of production of IL-12 in cultured cells—which could explain the higher risk. As Luciano Adorini (of Roche Milano Ricerche, in Milan, Italy) argues in an accompanying News & Views article, this study not only confirms the NOD mouse as a useful model; it may also lead to a better understanding of other autoimmune diseases and validate immunotherapies currently under development.

Nature Genetics pp 159 - 166 and pp 132 - 134

Infertility due to premature ovarian failure (POF) is a relatively common disorder, affecting an estimated 1% of women. POF typically manifests itself in the cessation of menses before age 40, accompanied by elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). It is known to result from a variety of defects, including a lower-than-normal complement of follicles, increased follicular loss, or so-called 'resistant ovaries', in which follicles no longer mature and ovulate in response to FSH and LH. Although autoimmunity and irradiation are known causes of POF, the importance of genetic components has been suggested both by the finding of affected families and by its association with a variety of X-chromosome abnormalities.

Giuseppe Pilia, of the University of Cagliari (Italy), along with an international group of collaborators in Belgium, France, the United States, and elsewhere in Italy, have now identified an autosomal gene that, when mutated, results in POF. The analysis of a syndrome characterized by an odd assortment of effects was the key to their finding. The syndrome, BPES type I, involves craniofacial abnormalities, eyelid defects and female infertility due to ovarian failure. Following up on previous studies in which a small region on chromosome 3 was identified as the region in which the critical gene is located, the researchers scrutinized two candidate genes, one of which, FOXL2, was found to be mutated in each affected member of four different type I BPES families. Consistent with ovarian dysfunction, FOXL2 was found to be expressed almost exclusively in the ovary in adult humans. In mice, the gene is expressed at high levels in developing eyelids and in the follicle cells that surround and nourish the oocytes, suggesting that it is in some way required for the development and maintenance of the follicles.

As Robyn Prueitt and Andrew Zinn (University of Texas Southwestern Medical School, Dallas) point out in an accompanying News & Views article, several promising lines of investigation are now apparent. FOXL2 encodes a protein known as a transcription factor, which regulates the action of other genes. A number of peptide growth factors are co-expressed with FOXL2 in the ovary; the genes encoding one or more of these factors now represent candidate targets of FOXL2, and may turn out to be the critical medatior(s) of ovarian dysfunction. The production of a Foxl2-deficient mouse undoubtedly will be an important step toward identifying the precise mechanism whereby FOXL2 promotes the viability of ovarian follicles and prevents ovarian failure.

Nature Genetics pp 153 - 154

It has been known for some years now that fetuses and newborn animals produced after cloning and other embryo manipulations are not only at much greater risk of developmental defects, but are sometimes much larger than their uncloned counterparts. Lorraine Young, Ian Wilmut (of the Roslin Institute) and colleagues now provide a clue as to why this is so. They compared the levels of the receptor of a protein that influences growth (an insulin growth factor receptor; IGF2R) between large, fetal sheep from 'test tube'-cultured embryos and those of 'normal' fetuses of the same age. The levels of IGF2R were indeed much lower in the large, cultured fetuses—30-60% lower&3151;than the normal fetuses. Young and colleagues speculate that these fetuses are bigger because there is less IGF2R to inhibit other factors that keep growth in check in the fetus. They went on to analyse the IGF2R gene and found that it lacks a common type of chemical modification (known as methylation) which is known to be involved in determining the 'volume' at which some genes that influence growth are set. The findings support the hypothesis that the methylation of DNA of embryo-manipulated animals is prone to disruption—and the argument that cloned embryos should be screened for such disruptions before their implantation into surrogate mothers.