Context: The majority of mutations responsible for IGHD II lead to dominant negative deleteriously increased levels of the GH1 exon 3 skipped transcripts.

Objective: The aim of this study was the characterization of the molecular defect causing a familial case of IGHD II.

Patients: A 2 yr old child and her mother with severe growth failure at diagnosis (-5.8 SDS and -6.9 SDS respectively) and IGHD were investigated for the presence of GH1 mutations.

Results: We identified a novel 22 bp deletion in IVS3 (IVS3 del+56-77) removing the putative branch point sequence (BPS). Analysis of patients' lymphocyte mRNA showed an excess exon 3 skipping. The mutated allele transfected into rat pituitary cells produced four differently spliced products: the exon 3 skipped mRNA as the main product and lower amounts of the full-length cDNA and of two novel mRNA aberrant isoforms, one deleted of the first 86 bases of exon 4 and the other lacking the entire exon 4. A mutagenized construct lacking exclusively the 7 pb of the BPS only generated the exon 4 skipped and the full-length isoforms. The presence of the full lenght transcript in the absence of the canonical BPS, points to an alternative BPS in IVS3.

Conclusion: The IVS3 del+56-77 mutation, causing IGHD II in this family, has two separate effects on mRNA processing : i) exon 3 skipping, analogous to most described cases of IGHD II. This effect is likely caused by the reduction in size of the IVS3. ii) partial or total exon 4 skipping, due to the removal of the BPS.