Conclusion
The molecular diagnosis of PAIS remains challenging. The genomic effect of retrotransposon mobilization should be considered a possible molecular cause of AIS and other AR diseases.
Objective
To identify the genetic etiology of AIS in a large multigenerational family with the PAIS phenotype. Participants: Nine affected individuals with clinical and laboratory findings consistent with PAIS and a normal exonic AR sequencing. Settings: Endocrine clinic and genetic institute from two academic referral centers. Design: Analysis of whole exons of the AR gene, including splicing regions, was performed, followed by sequencing of the 5'untranslated region (UTR) of the AR gene. Detailed phenotyping was performed at the initial diagnosis and long-term follow-up, and circulating levels of steroid gonadal hormones were measured in all affected individuals. AR expression was measured using RT-PCR and cultured fibroblasts.
Results
All 46,XY family members with PAIS had inherited, in hemizygosity, a complex defect (∼1100 bp) in the 5'UTR region of the AR surrounded by a duplicated 18-bp sequence (target site duplication). This sequence is 99.7% similar to an active, long, interspersed element present on the X chromosome (AC002980; Xq22.2), which was inserted in the 5'UTR of the AR gene, severely reducing AR expression and leading to PAIS.