Dataset Information

Mobile DNA in Endocrinology: LINE-1 Retrotransposon Causing Partial Androgen Insensitivity Syndrome.

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 (?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.

SUBMITTER: Batista RL

PROVIDER: S-EPMC6834070 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Mobile DNA in Endocrinology: LINE-1 Retrotransposon Causing Partial Androgen Insensitivity Syndrome.

Batista Rafael Loch RL Yamaguchi Katsumi K Rodrigues Andresa di Santi ADS Nishi Mirian Yumie MY Goodier John L JL Carvalho Luciani Renata LR Domenice Sorahia S Costa Elaine M F EMF Kazazian Haig H HH Mendonca Berenice Bilharinho BB

The Journal of clinical endocrinology and metabolism 20191201 12

<h4>Context</h4>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 ...[more]

PMID: 31393562

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Project description:BackgroundAndrogens are critical in male external genital development. Alterations in the androgen sensitivity pathway have been identified in severely undermasculinized boys, and mutations of the androgen receptor gene (AR) are usually found in partial or complete androgen insensitivity syndrome (AIS).ObjectiveThe aim of this study was to determine whether even the most minor forms of isolated hypospadias are associated with AR mutations and thus whether all types of hypospadias warrant molecular analysis of the AR.Materials and methodsTwo hundred and ninety-two Caucasian children presenting with isolated hypospadias without micropenis or cryptorchidism and 345 controls were included prospectively. Mutational analysis of the AR through direct sequencing (exons 1-8) was performed. In silico and luciferase functional assays were performed for unreported variants.ResultsFive missense mutations of the AR were identified in 9 patients with glandular or penile anterior (n = 5), penile midshaft (n = 2) and penile posterior (n = 2) hypospadias, i.e., 3%: p.Q58L (c.173A>T), 4 cases of p.P392S (c.1174C>T), 2 cases of p.A475V (c.1424C>T), p.D551H (c.1651G>C) and p.Q799E (c.2395C>G). None of these mutations was present in the control group. One mutation has never been reported to date (p.D551H). It was predicted to be damaging based on 6 in silico models, and in vitro functional studies confirmed the lowered transactivation function of the mutated protein. Three mutations have never been reported in patients with genital malformation but only in isolated infertility: p.Q58L, p.P392S, and p.A475V. It is notable that micropenis, a cardinal sign of AIS, was not present in any patient.ConclusionAR mutations may play a role in the cause of isolated hypospadias, even in the most minor forms. Identification of this underlying genetic alteration may be important for proper diagnosis and longer follow-up is necessary to find out if the mutations cause differences in sexual function and fertility later in life.

Dataset Information

Mobile DNA in Endocrinology: LINE-1 Retrotransposon Causing Partial Androgen Insensitivity Syndrome.

Publications

Mobile DNA in Endocrinology: LINE-1 Retrotransposon Causing Partial Androgen Insensitivity Syndrome.

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