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Title: Mobile DNA in Endocrinology: LINE-1 Retrotransposon Causing Partial Androgen Insensitivity Syndrome
Authors: BATISTA, Rafael LochYAMAGUCHI, KatsumiRODRIGUES, Andresa di SantiNISHI, Mirian YumieGOODIER, John L.CARVALHO, Luciani RenataDOMENICE, SorahiaCOSTA, Elaine M. F.KAZAZIAN JR., Haig H.MENDONCA, Berenice Bilharinho
Citation: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v.104, n.12, p.6385-6390, 2019
Abstract: 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 (similar to 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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Artigos e Materiais de Revistas Científicas - FM/MCM
Departamento de Clínica Médica - FM/MCM

Artigos e Materiais de Revistas Científicas - HC/ICESP
Instituto do Câncer do Estado de São Paulo - HC/ICESP

Artigos e Materiais de Revistas Científicas - HC/ICHC
Instituto Central - HC/ICHC

Artigos e Materiais de Revistas Científicas - HC/IPq
Instituto de Psiquiatria - HC/IPq

Artigos e Materiais de Revistas Científicas - LIM/42
LIM/42 - Laboratório de Hormônios e Genética Molecular

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