The adenomatous polyposis coli (APC) protein is a tumor suppressor frequently involved in the development of inherited and sporadic colon cancers. Somatic mutations of the APC gene are found in 80% of all colon cancers. Inherited mutations result in familial adenomatous polyposis (FAP) as well as an attenuated form of this syndrome. FAP is characterized by the early age onset of hundreds to thousands of colonic adenomatous polyps and a virtual certainty of colon cancer unless the colon is removed. The attenuated form of FAP (AFAP) is characterized by fewer adenomas, later onset of adenomas and cancer, and a decreased lifetime cancer risk. We report a 37-year-old man with a history of more than 50 colonic adenomatous polyps, located predominately in the right colon. An insertion of a single thymidine between the second and third base pairs of intron 4 of the APC gene was identified (c.531+2_531+3insT). Monoallelic hybrid cells harboring a single copy of human chromosome 5 were generated from patient lymphoblasts. Sequencing of the APC cDNA product from these cells revealed a single RNA transcript with aberrant splicing in the mutant mRNA whereby exon 4 is deleted. The translational reading frame is shifted after codon 140 and a translational stop is generated predicting a truncated protein of 147 amino acids, thus indicating that the intronic mutation is disease causing. The lack of a secondary transcript from the mutant allele suggests that incomplete exon skipping is not the molecular mechanism behind the attenuated phenotype.
Background Gastro-intestinal (GI) intolerance is a frequently reported outcome in patients with kidney failure receiving maintenance dialysis and those who have received kidney transplants. Symptoms of GI intolerance (diarrhoea, constipation, bloating, abdominal pain, heart burn, and reflux) are associated with significant reduction in quality of life, morbidity, and increased used of healthcare resources. Having chronic kidney disease (CKD), together with related changes in diet and medication, may alter the gut microbiota and the microbial-derived uraemic metabolites that accumulate in kidney failure, and contribute to various complications including chronic diarrhoea, opportunistic infections, and drug-related colitis. Despite the high disease burden among patients with kidney replacement therapies, GI symptoms are often under-recognised and, consequently limited resources and strategies are devoted to the management of gastrointestinal complications in patients with CKD. Methods The CKD Bowel Health Study is a multi-centre mixed-methods observational longitudinal study to better understand the bowel health and GI symptom management in patients with CKD. The program comprises of a longitudinal study that will assess the burden and risk factors of GI intolerance in patients treated with maintenance dialysis; a semi-structured interview study that will describe experiences of GI intolerance (including symptoms, treatment, self-management) in transplant candidates and recipients; and a discrete choice experience to elicit patient preferences regarding their experiences and perspectives of various intervention strategies for the management of GI symptoms after kidney transplantation. Discussion This proposed program of work aims to define the burden the GI intolerance in patients with kidney failure and generate evidence on the patients’ experiences of GI intolerance and their perspectives on their clinical and own management strategies of these symptoms, ensuring a patient-centred approach to guide clinical decision making and to inform the best study design for intervention trials. Trial registration This study is registered on the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000548831. This study has been approved by the Western Sydney Local Health District Human Research Ethics Committee of New South Wales Health (HREC ETH03007). This study is supported by a National Health and Medical Research Council (NHMRC) Australia Investigator Grant (APP1195414), and an NHMRC Australia Postgraduate Scholarship (APP2005244).
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