Endocrine Abstracts

Ectopic (or ‘illegitimate’) transcripts, which have been widely used to study disease-causing mutations when samples from the appropriate tissue cannot be obtained, are generally faithful representations of the normal tissue-specific counterparts. Here, we report the occurrence of ectopic transcripts of the hepatocyte nuclear factor-1 beta (HNF-1β) gene, mutations of which may result in maturity onset diabetes of the young type 5 (MODY5), the renal cysts and diabetes (RCAD) syndrome, and familial juvenile hyperuricaemic nephropathy (FJHN). We identified a donor splice site (IVS2nt+1g>a) HNF-1β mutation in a proband with FJHN, and whilst investigating the functional consequences in Epstein–Barr virus transformed lymphoblastoids, detected the occurrence of ectopic HNF-1β transcripts that are not representative of the normal tissue-specific counterparts. Thus, two such novel splice variants resulting from use of a pseudo splice donor site within exon 2, were identified in the FJHN patient and 5 normals. These were not detected in RNA obtained from normal liver, kidney, thymus or spleen, thereby indicating that their occurrence in the lymphoblastoids is consistent with an infidelity in ectopic transcription. Awareness of such infidelity of ectopic transcription, which has been previously reported for dystrophin and COL4A5 only, is important to ensure the correct interpretation of the functional consequences of DNA sequence variants identified in patients with metabolic and endocrine disorders.