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A study was conducted to identify mutations in MAP3K1 that cause downstream alterations in the MAP kinase signaling pathway in two familial and two sporadic cases of 46,XY disorders of sex development (DSD) in humans. The mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicated the MAP kinase signaling pathway in normal human sex determination.

Mammalian sex-determination is dependent on Sry, a Y-chromosome gene that leads to testes being developed instead of ovaries. Dax1 is a gene that encodes one of the superfamily of nuclear hormone receptors. This gene could be involved in human sex-reversal syndrome, where XY individals become females. XY mice show a delay in the development of the testes if they have additional copies of Dax1. Complete sex reversal can be seen if the transgene is tested against Sry's weak alleles. Dax1 appears to be the main cause of dosage-responsible sex-reversal, and could be the sole cause.

Deletions of the DAX-1 gene in patients and adrenal hypoplasia congenita (AHC) and analysis of point mutations in the coding region in DNA of the patients confirm that the DAX-1 gene causes X-linked AHC and the related hypogonadotropic hypogonadism (HHG). The DAX-1 gene has different point mutations and exhibits genetic heterogeneity or differential expression. This gene is characterized by a small size and a two exon structure.

A study of patients with X-linked adrenal hypoplasia congenita (AHC) reveals that the DAX-1 gene is responsible for AHC and the related hypogonadotrophic hypogonadism. This gene is deleted and mutated in AHC patients and codes for a new member of the nuclear hormone receptor superfamily containing a distinct DNA-binding domain. DAX-1 binds to retinoic acid (RA) responsive elements to demodulate transcriptional activation by RA receptors.

Kallmann's syndrome is characterized by a variety of neurological disorders, anosmia (inability to smell), and imbalances caused by reduction in the size and function of the gonads as a result of reduced secretion of pituitary hormones. The anosmia is caused by the absence of the olfactory bulbs, which receive nerve signals from the olfactory nerve, and the tracts that then carry olfactory information into the brain. The gene that is defective in Kallmann's syndrome is located on the X chromosome, specifically Xp22.3. In many cases, the region of the chromosome containing the gene is simply deleted. This is one of the few genes on the X chromosome that is represented on the Y chromosome as well. Furthermore, this gene seems to be similar in a great many species, suggesting that it may serve an especially important role. Researchers have now used techniques of molecular biology to study this gene in detail. The gene is deleted in patients with Kallmann's disease; sequencing of the gene from health subjects reveals that it is similar to specific genes for molecules that are critical in brain development. These molecules are thought to play an important role in the contact between cells of the developing nervous system; it is only by establishing proper contacts that cells of the nervous system and nerve fibers find their proper locations and establish correct interconnections. The similarity between these molecules and the gene involved in Kallmann's disease strongly suggests that the latter gene may be performing similar functions. Kallmann's disease appears to result from a defect in the normal migration of cells in the olfactory system and a defect in the normal migration of cells in the hypothalamus, which controls the release of the pituitary hormones. Several neurological deficits and syndromes are though to result from abnormalities in neuronal migration; Kallmann's syndrome may be the first condition in which the actual molecular basis of the abnormality has been identified. (Consumer Summary produced by Reliance Medical Information, Inc.)

Duplications in the ~2 Mb desert region upstream of SOX9 at 17q24.3 may result in familial 46,XX disorders of sex development (DSD) without any effects on the XY background. A balanced translocation with its breakpoint falling within the same region has also been described in one XX DSD subject. We analyzed, by conventional and molecular cytogenetics, 19 novel SRY-negative unrelated 46,XX subjects both familial and sporadic, with isolated DSD. One of them had a de novo reciprocal t(11;17) translocation. Two cases carried partially overlapping 17q24.3 duplications ~500 kb upstream of SOX9, both inherited from their normal fathers. Breakpoints cloning showed that both duplications were in tandem, whereas the 17q in the reciprocal translocation was broken at ~800 kb upstream of SOX9, which is not only close to a previously described 46,XX DSD translocation, but also to translocations without any effects on the gonadal development. A further XX male, ascertained because of intellectual disability, carried a de novo cryptic duplication at Xq27.1, involving SOX3. CNVs involving SOX3 or its flanking regions have been reported in four XX DSD subjects. Collectively in our cohort of 19 novel cases of SRY-negative 46,XX DSD, the duplications upstream of SOX9 account for ~10.5% of the cases, and are responsible for the disease phenotype, even when inherited from a normal father. Translocations interrupting this region may also affect the gonadal development, possibly depending on the chromatin context of the recipient chromosome. SOX3 duplications may substitute SRY in some XX subjects. [ABSTRACT FROM AUTHOR]

Background: Up to now, two loci have been involved in XX sex-reversal in mammals following loss-of-function mutations, PIS (Polled Intersex Syndrome) in goats and R-spondin1 (RSPO1) in humans. Here, we analyze the possible interaction between these two factors during goat gonad development. Furthermore, since functional redundancy between different R-spondins may influence gonad development, we also studied the expression patterns of RSPO2, 3 and 4. Results: Similarly to the mouse, RSPO1 shows a sex-dimorphic expression pattern during goat gonad development with higher levels in the ovaries. Interestingly, the PIS mutation does not seem to influence its level of expression. Moreover, using an RSPO1 specific antibody, the RSPO1 protein was localized in the cortical area of early differentiating ovaries (36 and 40 dpc). This cortical area contains the majority of germ cell that are surrounded by FOXL2 negative somatic cells. At latter stages (50 and 60 dpc) RSPO1 protein remains specifically localized on the germ cell membranes. Interestingly, a time-specific relocation of RSPO1 on the germ cell membrane was noticed, moving from a uniform distribution at 40 dpc to a punctuated staining before and during meiosis (50 and 60 dpc respectively). Interestingly, also RSPO2 and RSPO4 show a sex-dimorphic expression pattern with higher levels in the ovaries. Although RSPO4 was found to be faintly and belatedly expressed, the expression of RSPO2 increases at the crucial 36 dpc stage, as does that of FOXL2. Importantly, RSPO2 expression appears dramatically decreased in XX PIS-/- gonads at all three tested stages (36, 40 and 50 dpc). Conclusion: During goat ovarian development, the pattern of expression of RSPO1 is in agreement with its possible anti-testis function but is not influenced by the PIS mutation. Moreover, our data suggest that RSPO1 may be associated with germ cell development and meiosis. Interestingly, another RSPO gene, RSPO2 shows a sex-dimorphic pattern of expression that is dramatically influenced by the PIS mutation. [ABSTRACT FROM AUTHOR]