The cytochrome P450 aromatase lacking exon 5 is associated with a phenotype of nonclassic aromatase deficiency and is also present in normal human steroidogenic tissues.

[aromatase deficiency]

The previously described c 655 G >A mutation of the human cytochrome P 450 aromatase gene (P 450 aro , CYP 19 ) results in aberrant splicing due to disruption of a donor splice site . To explain the phenotype of partial aromatase deficiency observed in a female patient described with this mutation , molecular consequences of the c 655 G >A mutation were investigated .To investigate whether the c 655 G >A mutation causes an aberrant spliced mRNA lacking exon 5 (-Ex 5 ), P 450 aro RNA was analysed from the patient 's lymphocytes by reverse transcription polymerase chain reaction (RT-PCR ) and by splicing assays performed in Y 1 cells transfected with a P 450 aro -Ex 5 expression vector . Aromatase activity of the c 655 G >A mutant was predicted by three dimensional (3 D ) protein modelling studies and analysed in transiently transfected Y 1 cells . Exon 5 might be predicted as a poorly defined exon suggesting a susceptibility to both splicing mutations and physiological alternative splicing events . Therefore , expression of the -Ex 5 mRNA was also assessed as a possibly naturally occurring alternative splicing transcript in normal human steroidogenic tissues .An aromatase deficient girl was born with ambiguous genitalia . Elevated serum LH , FSH and androgens , as well as cystic ovaries , were found during prepuberty . At the age of 8 .4 years , spontaneous breast development and a 194 .6 pmol /l serum oestradiol level was observed .The -Ex 5 mRNA was found in lymphocytes of the P 450 aro deficient girl and her father , who was a carrier of the mutation . Mutant minigene expression resulted in complete exon 5 skipping . As expected from 3 D protein modelling , -Ex 5 cDNA expression in Y 1 cells resulted in loss of P 450 aro activity . In addition , the -Ex 5 mRNA was present in placenta , prepubertal testis and adrenal tissues .Alternative splicing of exon 5 of the CYP 19 gene occurs in the wild type (WT ) as well as in the c 655 G >A mutant . We speculate that for the WT it might function as a regulatory mechanism for aromatization , whereas for the mutant a relative prevalence of the shorter over the full-length protein might explain the phenotype of partial aromatase deficiency .

Diseases
Validation

Diseases presenting "relative prevalence" symptom

aromatase deficiency

liposarcoma

well-differentiated liposarcoma

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