Novel scavenger receptor gene is differentially expressed in the embryonic and adult mouse testis.

In an effort to understand the mechanisms that underpin gonadal differentiation at the time of sex determination, we identified a cDNA encoding a putative novel testis expressed scavenger receptor, Tesr. Based on its domain structure, we hypothesize that the function of Tesr is similar to that of other scavenger receptors that play roles in phagocytosis of apoptotic cells, cell-cell adhesion, and defense. Tesr mRNA was detected in fetal mouse gonads of both sexes at 11.5 days post coitum (dpc). From 12.0 dpc, Tesr expression rapidly decreased in the female and was maintained in the male. Expression was seen in embryonic mouse sites other than the testis, such as in brain, eye, head, heart, neural arch, and cartilage primordium. Tesr expression in the newborn testis was faint to undetectable, but it increased from 2 days postpartum (dpp) until 15 dpp and was found in a subset of interstitial cells and in germ and Sertoli cells. Tesr mRNA in the adult mouse testis was observed in Sertoli cells, spermatogonia, spermatocytes, round spermatids, and in a subset of interstitial cells. We conclude that Tesr is differentially expressed in the male vs. female embryonic gonad and is expressed in both the ovary and the testes postnatally after 2 dpp.

SOX14 is a candidate gene for limb defects associated with BPES and Möbius syndrome.

Members of the SOX gene family encode proteins with homology to the HMG box DNA-binding domain of SRY, the Y-linked testis-determining gene. SOX genes are expressed during embryogenesis and are involved in the development of a wide range of different tissues. Mutations in SRY, SOX9 and SOX10 have been shown to be responsible for XY sex reversal, campomelic dysplasia and Waardenburg-Hirschsprung disease, respectively. It is likely that mutations in other SOX genes are responsible for a variety of human genetic diseases. SOX14 has been identified from a human genomic library and the mouse and chicken sequences obtained by polymerase chain reaction amplification. The SOX14 amino acid sequence is highly conserved across these species, suggesting an important role for this protein in vertebrate development. SOX14 is expressed in the neural tube and apical ectodermal ridge of the developing chicken limb. This is the only SOX gene known to be expressed in the apical ectodermal ridge, a structure that directs outgrowth of the embryonic limb bud. Human SOX14 is localised to a 1.15-Mb yeast artificial chromosome on chromosome 3q23, close to loci for BPES (blepharophimosis, ptosis, epicanthus inversus syndrome) and Mobius syndrome. Although SOX14 maps outside these loci, its expression pattern and chromosomal localisation suggest that it is a candidate gene for the limb defects frequently associated with these syndromes.

Germline and somatic abnormalities of chromosome 7 in Wilms' tumor.

Although a gene (WT1) located at chromosome 11p13 is implicated in the development of Wilms' tumor (WT), there is evidence that genes on other chromosomes are also involved. A WT patient presented with a constitutional balanced translocation between chromosomes 1 and 7, t(1;7)(q42;p15), the breakpoints of which could represent a WT predisposition gene in this patient. Cytogenetic analysis of the tumor from this patient revealed an acquired abnormality of the other chromosome 7, resulting in an isochromosome of the long arm and a 46,XY,t(1;7)(q42;p15)c,i(7)(q10) karyotype. The regions of the translocation breakpoints were investigated in a series of 24 WTs using Southern blot analysis. This confirmed the monosomy of 7p and trisomy of 7q in the tumor of the translocation patient, and in addition a loss of chromosome 7p alleles was identified in a WT of a bilaterally affected patient. In addition, two WTs were shown to have an extra copy of chromosome 7 alleles. Multiple copies of chromosome 1q alleles, probably resulting from secondary changes, were observed in two WTs, one of which was also associated with a trisomy of chromosome 7. These results indicate that 7p may contain a tumor suppressor gene involved in WT development, and that duplications of 7q also may play a role in WT development.

Low frequency of mutations in the WT1 coding region in Wilms' tumor.

A series of twenty unselected Wilms' tumors were analysed for alterations in the WT1 tumor suppressor gene. The entire coding region of WT1 was amplified by RNA-PCR, and then screened for mutations by single-strand conformational polymorphism analysis (SSCP). This method was shown to be capable of detecting point mutations in the WT1 gene, by using an experimentally produced mutation. A single mutation, a 226 bp intragenic deletion, was detected in a tumor from a patient with the WAGR syndrome. These results suggest that alterations in the WT1 gene may be involved in only a subset of Wilms' tumors, and that other loci need to be investigated as potential suppressor genes in sporadic Wilms' tumors.