Mobile DNA in Endocrinology: LINE-1 retrotransposon causing Partial Androgen Insensitivity Syndrome.

Abstract

CONTEXT\nAndrogen insensitivity syndrome (AIS) is the most common cause of disorders of sex development in 46,XY individuals. It is an X-linked condition that is usually caused by pathogenic allelic variants in the androgen receptor (AR) gene. The phenotype depends on the AR variant, ranging from severe undervirilization (complete AIS, CAIS) to several degrees of external genitalia undervirilization. However, while 90% of CAIS has AR mutations, this is only true for 40% of PAIS.\n\n\nOBJECTIVE\nTo identify the genetic etiology of AIS in a large multigenerational family with PAIS phenotype.\n\n\nPARTICIPANTS\nNine affected individuals with clinical and laboratory findings consistent with PAIS and a normal exonic AR sequencing.\n\n\nSETTINGS\nEndocrine clinic and genetic institute from two academic referral centers.\n\n\nDESIGN\nAnalysis of whole exons of the AR gene, including splicing regions, was performed, followed by sequencing of the 5 UTR region of the androgen receptor gene. Detailed phenotyping was performed at the time of initial diagnosis and long-term follow-up and circulating levels of steroid gonadal hormones were measured in all affected individuals. Expression of AR was measured by RT-PCR using cultured fibroblasts.\n\n\nRESULTS\nAll 46,XY family members with PAIS 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 (LINE-1) present on the X chromosome (AC002980; Xq22.2), which was inserted in the 5 UTR of the AR gene, severely reducing the AR expression, leading to PAIS.