SummaryOBJECTIVEHereditary vitamin D resistant rickets (HVDRR) is an autosomal recessive disorder resulting in target organ resistance to the actions of 1,25‐dihydroxyvitamin D3(1,25(OH)2D3). In many cases, this disorder has been shown to be due to mutations in the gene encoding vitamin D receptors (VDR). In a patient with characteristic features of this disorder, we investigated the functional defect and sequenced the coding region of the gene for mutations.DESIGNSkin fibroblasts from patient and control were used to measure binding of 1,25(OH)2D3and functional responses to the hormone. These cells were also used to prepare RNA from which cDNA was prepared and sequenced. Furthermore, genomic DNA was prepared from the fibroblasts and the intronlexon boundarles sequenced.PATIENTA child with classic features of HVDRR with alopecia diagnosed as having rickets due to resistance to 1,25(OH)2D3.MEASUREMENTSNuclear association of 1,25(OH)2D3was determined in patient and control cells and the functional response to 1,25(OH)2D3was assessed by measurement of 25‐hydroxyvitamln D‐24‐hydroxylase(24‐hydroxylase) activity. VDR cDNA and genomic DNA prepared from patient and control cells were sequenced.RESULTSCells from the patient with HVDRR had undetectable amounts of VDR compared to control cells and did not show induction of 24‐hydroxylase activity following treatment with 1,25(OH), D3. Sequencing of the VDR coding region after RT‐PCR of RNA revealed an absence of exon 4 in patient RNA which was not due to a deletion in genomic DNA but was caused by exon skipping during RNA processing. In addition, the deletion of exon 4 sequences from RNA leads to a frameshift in translation resulting in a premature stop codon. Amplification of genomic DNA around the intron/exon boundary of exon 4 revealed a point mutation in the 5’donor splice site of intron 4.CONCLUSIONIn this study, we have identified a novel mutation in the gene for vitamin D receptors in a patient with the Characteristic phenotype of hereditary vitamin D resistant rickets. The mutation at the + 5 position in intron 4 is most likely to cause skipping of exon 4