Genome-Wide Association Mapping in Dogs Enables Identification of the Homeobox Gene, NKX2-8, as a Genetic Component of Neural Tube Defects in Humans

Neural tube defects (NTDs) is a general term for central nervous system malformations secondary to a failure of closure or development of the neural tube. The resulting pathologies may involve the brain, spinal cord and/or vertebral column, in addition to associated structures such as soft tissue or skin. The condition is reported among the more common birth defects in humans, leading to significant infant morbidity and mortality. The etiology remains poorly understood but genetic, nutritional, environmental factors, or a combination of these, are known to play a role in the development of NTDs. The variable conditions associated with NTDs occur naturally in dogs, and have been previously reported in the Weimaraner breed. Taking advantage of the strong linkage-disequilibrium within dog breeds we performed genome-wide association analysis and mapped a genomic region for spinal dysraphism, a presumed NTD, using 4 affected and 96 unaffected Weimaraners. The associated region on canine chromosome 8 (pgenome  =3.0 × 10(-5)), after 100,000 permutations, encodes 18 genes, including NKX2-8, a homeobox gene which is expressed in the developing neural tube. Sequencing NKX2-8 in affected Weimaraners revealed a G to AA frameshift mutation within exon 2 of the gene, resulting in a premature stop codon that is predicted to produce a truncated protein. The exons of NKX2-8 were sequenced in human patients with spina bifida and rare variants (rs61755040 and rs10135525) were found to be significantly over-represented (p=0.036). This is the first documentation of a potential role for NKX2-8 in the etiology of NTDs, made possible by investigating the molecular basis of naturally occurring mutations in dogs

Urinary and sexual dysfunction after rectal cancer treatment

In light of the improving prognosis for patients with rectal cancer, the quality of functional outcome has become increasingly important. Despite the good functional results achieved by expert surgeons, large multicenter studies show that urogenital dysfunction remains a common problem after rectal cancer treatment. More than half of patients experience a deterioration in sexual function, consisting of ejaculatory problems and impotence in men and vaginal dryness and dyspareunia in women. Urinary dysfunction occurs in one-third of patients treated for rectal cancer. Surgical nerve damage is the main cause of urinary dysfunction. Radiotherapy seems to have a role in the development of sexual dysfunction, without affecting urinary function. Pelvic autonomic nerves are especially at risk in cases of low rectal cancer and during abdominoperineal resection. Data concerning nerve damage during laparoscopic surgery for resection of rectal cancer are awaited. Structured education of surgeons with regard to pelvic neuroanatomy, and systematic registration of identified nerves, could well be the key to improving functional outcome for these patients. Meanwhile, patients should be informed of all associated risks before their operation, and their functional status should be evaluated before and after surgery.Surgical oncolog