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Objective Mutations in DAX-1, an X-linked gene encoding an orphan nuclear receptor, have been associated with adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Here we describe two novel DAX-1 mutations, Y214X and I361T, associated with childhood-onset primary adrenal failure. We aimed at analysing their effects on protein localization, transcriptional activity and propose a structural-function relationship. Design We have directly sequenced the DAX-1 gene from PCR-amplified DNA. The effect of the mutations on protein localization was assessed by immunocytochemistry in transfected cells. The impact of mutations on transcriptional activity was determined by transfection using a StAR promoter-luciferase reporter system. Results The mutation Y214X produces a protein lacking the C-terminal half of DAX-1. The other one, I361T, affects a highly conserved amino acid within the putative ligand-binding domain. The mutant Y214X displayed a wild-type subcellular localization while I361T was partially retained in the cytoplasm. Both mutants retained subtantial transcriptional repressive activity, compared to mutants producing early onset adrenal failure. Interestingly, I361T displayed similar in vitro transcriptional repressive activity to the mutant I439S previously described in a case of late-onset AHC. This shows that molecular alterations of DAX-1 leading to similar in vitro activities may result in very different ages of onset of adrenal failure, which suggests that additional genetic and epigenetic factors are important in determining the clinical course of AHC. Conclusions Our results help the understanding of structure–function relationships in the DAX-1 molecule, suggesting that the N-terminal domain is relatively autonomous and add credence to presumed molecular interactions within ligand binding domain of the protein. [ABSTRACT FROM AUTHOR]

The allelic variability at six Y-chromosome-specific polymorphisms (YAP, DYS19, DYS389-I, DYS390, DYS391, and DYS392) was used to generate male-specific haplotypes in 333 males representing 12 population samples from the region around the Mediterranean sea. Extreme interindividual variation was observed, as more than 160 distinct Y-chromosome variants could be defined as six-locus haplotypes. Concomitant with this high variability, low levels of population genetic structure were observed. In particular, a "core" of populations directly facing the north and the east of the Mediterranean basin, from the Middle East to the Italian Peninsula, was found to be genetically undifferentiated. This observation, supported by a reanalysis of Y-specific binary polymorphisms in the same populations, suggests that at least part of the male-specific gene pools of these popula- tions has either a very recent common origin (that could be related with the Neolithic demic diffusion hypothesis), and/or that gene flow has played a significant role in shaping the patterns of genetic variability in this region. In agreement with both hypotheses, we found that the spatial distribution of DYS392 alleles revealed a marked differentiation between the East and the West of the Mediterranean area. Through the analysis of microsatellite variation, the time to the most recent common ancestor (TMRCA) of the YAP[sup +] sublineage 4 has been estimated. The estimations, based on two different data sets, turn out to be quite recent (7,000-11,000 YBP), suggesting that this lineage may have been first introduced into Southern Europe through Neolithic migrations from the Middle East. [ABSTRACT FROM AUTHOR]

We previously demonstrated that the gene tyke rescues the phenotype of a human mutant cell line unresponsive to α (IFN) and partially responsive to IFN-β. Here, we describe functional complementation of the mutant cells with the corresponding cDNA. To characterize the putative non-receptor protein tyrosine kinase encoded by the gene tyke and begin to understand its functioning, we have raised polyclonal antibodies against a segment of the protein. Using these, we have identified tyke as a 134-kDa protein which is rapidly and transiently phosphorylated on tyrosine in response to IFN-α/β and possesses an inducible kinase activity when tested in vitro. IFN-γ has no effect on the phosphorylation state of the protein. In agreement with previous genetic evidence, these results assign a role to tyke in the IFN-α/β signaling pathway and not in the IFN-γ pathway. Fractionation of cell lysates have helped to localize the bulk of the protein in the cytoplasm, with a minor fraction associated with the cell membrane. Both protein pools undergo activation upon short-term IFN treatment of intact cells. Through the study of the effect of pervanadate on the phosphorylation level and the activity of tyke, we conclude that activation of tyke by IFN-α does not require an intermediate regulatory tyrosine phosphatase. [ABSTRACT FROM AUTHOR]

Describes the genetic control mechanism which have involved in the determination of sex in fruit fly and nematode. Identification and isolation of mutations; Factors responsible for initiating testes formation; Measurement of the levels of X-linked transcripts; Inactivation of one of the two chromosomes during female development.

A letter to the editor is presented which describes a study that supports the notion that mutations in the coding region of FOXO3a are not a frequent cause of premature ovarian failure (POF).

The article focuses on the premature ovarian failure (POF) in women. POF leads to female infertility. This disease is characterized by high plasma gonadotrophins levels and amenorrhoea (among persons under 40 years). BMP15 mutation in a POF case led to genetic screening of a panel of women revealing further potentially pathogenic variants. The finding of the study and the effects of mutations are highlighted in the article.

The article focuses on the functionality of BMP15 as a growth factor encode by an X-linked gene which can be expressed by oocytes from early follicular developmental stages. It notes the demonstration of the relevance of BMP15 in reproduction in animal models. The hypothesis which emphasized the capability of insufficient processing of signal peptides of BMP15-Ser5Arg to affect normal secretion of protein and induce a dominant negative effect is mentioned.

A letter to the editor that discusses premature ovarian failure is presented.

Cloacal exstrophy is a rare malformation, belonging to a spectrum of birth defects, which, in order of severity, includes phallic separation with epispadias, pubic diastasis, bladder exstrophy, and cloacal exstrophy. This malformation overlaps the OEIS complex (O = omphalocele, E = bladder exstrophy, I = imperforate anus, S = spinal defects). The etiology of cloacal exstrophy is unknown to date. It may result from either a single defect of early blastogenesis or a defect of mesodermal migration during the primitive streak period. We report an infant with cloacal exstrophy, exomphalos, right kidney agenesis, ambiguous external genitalia, and axial hypotonia. The karyotype showed a de novo unbalanced translocation between the long arm of chromosome 9 and the long arm of chromosome Y resulting in a 9q34.1-qter deletion. Reviewing the literature, we did not find any observation of cloacal exstrophy associated with a structural chromosomal abnormality. The steroidogenic factor 1 (SF1) gene, included in the deleted region, was a good candidate gene but no pathogenic mutation was found by direct sequencing. We hypothesize that another gene, expressed early in embryogenesis and responsible for cloacal exstrophy, is present in the 9q34.1-qter region., (Copyright 2003 Wiley-Liss, Inc.)