A duplication in a patient with 46,XX ovo-testicular disorder of sex development refines the SOX9 testis-specific regulatory region to 24 kb.

A custom CGH microarray that covers the SOX9 regulatory region. Log2 ratio scatterplot showing individual data points. Blue box highlights copy number gain with 3' breakpoint region magnified.

Exome sequencing in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE ɛ4 allele increased the risk of disease (P=0.0001), conferred a shorter disease duration (P=0.043) and earlier age of death (P=0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE ɛ4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.

DMRT1 is required for Müllerian duct formation in the chicken embryo.

DMRT1 is a conserved transcription factor with a central role in gonadal sex differentiation. In all vertebrates studied, DMRT1 plays an essential function in testis development and/or maintenance. No studies have reported a role for DMRT1 outside the gonads. Here, we show that DMRT1 is expressed in the paired Müllerian ducts in the chicken embryo, where it is required for duct formation. DMRT1 mRNA and protein are expressed in the early forming Müllerian ridge, and in cells undergoing an epithelial to mesenchyme transition during duct morphogenesis. RNAi-mediated knockdown of DMRT1 in ovo causes a greatly reduced mesenchymal layer, which blocks caudal extension of the duct luminal epithelium. Critical markers of Müllerian duct formation in mammals, Pax2 in the duct epithelium and Wnt4 in the mesenchyme, are conserved in chicken and their expression disrupted in DMRT1 knockdown ducts. We conclude that DMRT1 is required for the early steps of Müllerian duct development. DMRT1 regulates Müllerian ridge and mesenchyme formation and its loss blocks caudal extension of the duct. While DMRT1 plays an important role during testis development and maintenance in many vertebrate species, this is the first report showing a requirement for DMRT1 in Müllerian duct development.

The molecular genetics of ovarian differentiation in the avian model.

In birds as in mammals, sex is determined at fertilization by the inheritance of sex chromosomes. However, sexual differentiation - development of a male or female phenotype - occurs during embryonic development. Sex differentiation requires the induction of sex-specific developmental pathways in the gonads, resulting in the formation of ovaries or testes. Birds utilize a different sex chromosome system to that of mammals, where females are the heterogametic sex (carrying Z and W chromosomes), while males are homogametic (carrying 2 Z chromosomes). Therefore, while some genes essential for testis and ovarian development are conserved, important differences also exist. Namely, the key mammalian male-determining factor SRY does not exist in birds, and another transcription factor, DMRT1, plays a central role in testis development. In contrast to our understanding of testis development, ovarian differentiation is less well-characterized. Given the presence of a female-specific chromosome, studies in chicken will provide insight into the induction and function of female-specific gonadal pathways. In this review, we discuss sexual differentiation in chicken embryos, with emphasis on ovarian development. We highlight genes that may play a conserved role in this process, and discuss how interaction between ovarian pathways may be regulated.

Effects of ethanol on mature offspring of mice given ethanol during pregnancy.

Male offspring of mice maintained on isocaloric liquid diets containing either 20% ethanol or sucrose derived calories during pregnancy were tested on their ability to discriminate different ethanol doses as adults. They were trained to lever-press for a food reward on each of two levers in an operant chamber, and were then maintained on an FR20 reinforcement schedule. After response rates stabilized, ethanol discrimination training was initiated by reinforcing only responses made on the drug appropriate-lever after i.p. injections of ethanol (1.0 g/kg) or water. After learning to discriminate the 1.0 g dose, the animals' ability to discriminate doses of 0.25, 0.50, 0.75, 1.0, and 1.5 g/kg was assessed by determining the percentage of responses made on the drug lever during a 2-min test period. Compared to sucrose controls, mice exposed to alcohol in utero learned the lever response more slowly and were less responsive to injected ethanol as evidenced by a reduced effect of the drug on response rates and by a reduction in their ability to discriminate the presence of injected ethanol. The results indicate that prenatal ethanol exposure can have long term consequences which reduce the effects of ethanol in fully mature animals.