TY - JOUR
T1 - Mobile DNA in Endocrinology
T2 - LINE-1 Retrotransposon Causing Partial Androgen Insensitivity Syndrome
AU - Batista, Rafael Loch
AU - Yamaguchi, Katsumi
AU - Rodrigues, Andresa Di Santi
AU - Nishi, Mirian Yumie
AU - Goodier, John L.
AU - Carvalho, Luciani Renata
AU - Domenice, Sorahia
AU - Costa, Elaine M.F.
AU - Kazazian, Haig H.
AU - Mendonca, Berenice Bilharinho
N1 - Funding Information:
The present study was partially supported by Grant 303002/2016-6 to B.B.M. H.H.K. was supported by Grant 5R01GM099875-08 from the National Institute of General Medical Studies, National Institutes of Health, and J.L.G. by Grant 1R21AG056840-01A1 from the National Institute on Aging, National Institutes of Health.
Publisher Copyright:
Copyright © 2019 Endocrine Society.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Context: Androgen insensitivity syndrome (AIS) is the most common cause of disorders of sex development in 46,XY individuals. It is an X-linked condition 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) to several degrees of external genitalia undervirilization. Although 90% of those with complete AIS will have AR mutations, this will only be true for 40% of those with partial AIS (PAIS). 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. 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.
AB - Context: Androgen insensitivity syndrome (AIS) is the most common cause of disorders of sex development in 46,XY individuals. It is an X-linked condition 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) to several degrees of external genitalia undervirilization. Although 90% of those with complete AIS will have AR mutations, this will only be true for 40% of those with partial AIS (PAIS). 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. 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.
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U2 - 10.1210/jc.2019-00144
DO - 10.1210/jc.2019-00144
M3 - Article
C2 - 31393562
AN - SCOPUS:85074673494
VL - 104
SP - 6385
EP - 6390
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 12
ER -