Deletion within theCYP17 Gene Together with Insertion of Foreign DNA Is the Cause of Combined Complete 17α-Hydroxylase/17,20-Lyase Deficiency in an Italian Patient

Abstract

The molecular basis of 17 alpha-hydroxylase/17,20-lyase deficiency syndrome in a 14-yr-old 46,XY Italian patient was investigated by amplification, subcloning, and sequencing of specific exonic sequences from genomic DNA samples. A homozygous mutation, consisting of a 518-basepair (bp) deletion combined with a 469-bp insertion, was identified in the CYP17 gene of the patient. The deletion spans much of exon II, the whole intron 2, and a portion of exon III. A part (156 bp) of the inserted sequence shows 95.5% identity to the nuclear antigen-binding site on Marek disease virus DNA and sequences found in rearranged mitochondrial DNA of rat hepatoma cells. A similar degree of sequence identity (99%) was also found between the above sequences and part of the lac operon of E. coli. The inserted sequence is lacking the BamHI site in intron 2 of CYP17 and contains an in-frame stop codon (TAA). Thus, the mutated gene encodes a truncated nonfunctional steroid hydroxylase, giving rise to symptoms associated with complete combined 17 alpha-hydroxylase/17,20-lyase deficiency. The family history revealed that the patient is the child of a consanguineous marriage and has two genotypically and phenotypically female sisters also suffering from symptoms of the disease. Investigation of genomic DNA from these sisters revealed that in each case both CYP17 alleles contained the same mutation. On the other hand, the parents were found to be heterozygous for this mutation. The insertion could not be found in DNA from normal individuals or in the CYP17 gene of other Italian patients with the 17 alpha-hydroxylase deficiency syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of a Novel Large <b><i>CYP17A1 </i></b>Deletion by MLPA Analysis in a Family with Classic 17α-Hydroxylase Deficiency

“…The largest reported genomic rearrangement in CYP17A1 involves a deletion of 518 bp (most of exon 2 and part of exon 3) with an insertion of 469 bp. This leads to an N-terminal disruption of CYP17A1 causing complete 17OHD [Biason et al, 1991]. The deletion described in our paper involves exons 1-6, confirming the severe phenotype of our patients with complete 17OHD.…”

Bases Moleculares da Hiperplasia Adrenal Congênita

“…Doze deleções que afetam o gene CYP17 (31% das mutações) promovem frameshift, com conseqüente expressão de uma proteína muito truncada. A maior mutação descrita no gene CYP17 é uma extensa deleção que acomete três membros de uma mesma família italiana (83). A deleção de 518 pb associada à inserção de 469 pb de DNA não humano acomete o exon II, todo o intron II e parte do exon III.…”

O espectro das síndromes de hipertensão esteróide na infância e adolescência

“…Até o momento, foram descritas 30 diferentes mutações em várias famílias, incluido pequenas inserções (68,69), deleções de codons simples (70), duplicações de até 7 pares de bases (68), e apenas um caso de grande deleção com inserção de DNA não homólogo (71). Quatro novas mutações foram recentemente detectadas nas 18 famílias brasileiras estudadas (Costa-Santos, Kater & Auchus, dados não publicados).…”