Phát hiện đột biến mới trên Gen AR ở bệnh nhân mắc hội chứng kháng androgen

Viet Nam ◽

Hội chứng kháng androgen (AIS - Androgen Insensitivity Syndrome) là một trong những rối loạn di truyền phổ biến nhất ảnh hưởng đến phát triển giới tính trước khi sinh và dậy thì ở trẻ. Về di truyền, những trẻ này là nam giới, nhưng khi sinh ra có kiểu hình một phần hoặc hoàn toàn là nữ. Xét nghiệm gen AR là phương pháp xác định chính xác nguyên nhân gây hội chứng kháng androgen. Mục tiêu của nghiên cứu là xác định kiểu gen AR đột biến trên bệnh nhân nam mắc hội chứng kháng androgen có kiểu hình nữ và kiểu gen của mẹ bệnh nhân bằng phương pháp giải trình tự gen trực tiếp. Kết quả đã phát hiện một đột biến hoàn toàn mới c.2246C>T (p.Ala749Val) trên exon 5 của gene AR, đột biến chưa được báo cáo trong dữ liệu ngân hàng gen của thế giới. Đột biến ở dạng bán hợp tử được di truyền từ mẹ của bệnh nhân ở dạng dị hợp tử. Kết quả này giúp gia đình định hướng giới tính phù hợp cho bệnh nhân. Đồng thời, nghiên cứu đóng góp thêm dữ liệu đột biến mới về gen AR trong quần thể bệnh nhân AIS người Việt Nam, góp phần quản lý bệnh và tư vấn di truyền trước sinh cho gia đình người bệnh.

Abstract #902: The Wide Spectrum of Androgen Insensitivity Syndrome

Endocrine Practice ◽

10.1016/s1530-891x(20)42782-x ◽

2015 ◽

Vol 21 ◽

pp. 178

Author(s):

Shwetha Mallesara Sudhakar ◽

Shahla Nadereftekhari

Keyword(s):

Wide Spectrum ◽

Next generation sequencing and functional characterization of the androgen receptor (AR) gene in patients with androgen insensitivity syndrome (AIS) and controls

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0035-1547779 ◽

2015 ◽

Vol 122 (03) ◽

Author(s):

N Hornig ◽

HU Schweikert ◽

M Ukat ◽

AE Kulle ◽

M Welzel ◽

...

Keyword(s):

Androgen Receptor ◽

Next Generation Sequencing ◽

Functional Characterization ◽

Next Generation ◽

Androgen Insensitivity ◽

Generation Sequencing

Partial androgen insensitivity syndrome with predominantly male phenotype – clinical, endocrine, and genetic findings in 37 cases

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-2004-819289 ◽

2004 ◽

Vol 112 (S 1) ◽

Author(s):

W Birnbaum ◽

PM Holterhus ◽

O Hiort

Keyword(s):

Partial Androgen Insensitivity Syndrome

Androgen Insensitivity ◽

Male Phenotype ◽

Complete androgen insensitivity syndrome and breastfeeding

Endocrine Abstracts ◽

10.1530/endoabs.48.we1 ◽

2017 ◽

Author(s):

Gemma Fraterrigo ◽

William Drake

Keyword(s):

Complete Androgen Insensitivity Syndrome ◽

Faculty Opinions recommendation of Long-term followup and comparison between genotype and phenotype in 29 cases of complete androgen insensitivity syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1126902.584011 ◽

2008 ◽

Author(s):

Bradley Kropp

Keyword(s):

Complete Androgen Insensitivity Syndrome ◽

Complete Androgen Insensitivity Syndrome: From Bench to Bed

International Journal of Molecular Sciences ◽

10.3390/ijms22031264 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1264

Author(s):

Nina Tyutyusheva ◽

Ilaria Mancini ◽

Giampiero Igli Baroncelli ◽

Sofia D’Elios ◽

Diego Peroni ◽

...

Keyword(s):

Receptor Gene ◽

Hormone Replacement ◽

Basic Research ◽

Well Being ◽

Androgen Receptor Gene ◽

Primary Amenorrhea ◽

Complete Androgen Insensitivity Syndrome ◽

Complete androgen insensitivity syndrome (CAIS) is due to complete resistance to the action of androgens, determining a female phenotype in persons with a 46,XY karyotype and functioning testes. CAIS is caused by inactivating mutations in the androgen receptor gene (AR). It is organized in eight exons located on the X chromosome. Hundreds of genetic variants in the AR gene have been reported in CAIS. They are distributed throughout the gene with a preponderance located in the ligand-binding domain. CAIS mainly presents as primary amenorrhea in an adolescent female or as a bilateral inguinal/labial hernia containing testes in prepubertal children. Some issues regarding the management of females with CAIS remain poorly standardized (such as the follow-up of intact testes, the timing of gonadal removal and optimal hormone replacement therapy). Basic research will lead to the consideration of new issues to improve long-term well-being (such as bone health, immune and metabolic aspects and cardiovascular risk). An expert multidisciplinary approach is mandatory to increase the long-term quality of life of women with CAIS.

The FKBP4 Gene, Encoding a Regulator of the Androgen Receptor Signaling Pathway, Is a Novel Candidate Gene for Androgen Insensitivity Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms21218403 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8403

Author(s):

Erkut Ilaslan ◽

Renata Markosyan ◽

Patrick Sproll ◽

Brian J. Stevenson ◽

Malgorzata Sajek ◽

...

Keyword(s):

Androgen Receptor ◽

Signaling Pathway ◽

Gene Mutation ◽

Gene Mutations ◽

Partial Androgen Insensitivity Syndrome

Homologous Gene ◽

Gene Encoding ◽

Androgen Insensitivity ◽

Disorder Of Sexual Development ◽

Androgen insensitivity syndrome (AIS), manifesting incomplete virilization in 46,XY individuals, is caused mostly by androgen receptor (AR) gene mutations. Therefore, a search for AR mutations is a routine approach in AIS diagnosis. However, some AIS patients lack AR mutations, which complicates the diagnosis. Here, we describe a patient suffering from partial androgen insensitivity syndrome (PAIS) and lacking AR mutations. The whole exome sequencing of the patient and his family members identified a heterozygous FKBP4 gene mutation, c.956T>C (p.Leu319Pro), inherited from the mother. The gene encodes FKBP prolyl isomerase 4, a positive regulator of the AR signaling pathway. This is the first report describing a FKBP4 gene mutation in association with a human disorder of sexual development (DSD). Importantly, the dysfunction of a homologous gene was previously reported in mice, resulting in a phenotype corresponding to PAIS. Moreover, the Leu319Pro amino acid substitution occurred in a highly conserved position of the FKBP4 region, responsible for interaction with other proteins that are crucial for the AR functional heterocomplex formation and therefore the substitution is predicted to cause the disease. We proposed the FKBP4 gene as a candidate AIS gene and suggest screening that gene for the molecular diagnosis of AIS patients lacking AR gene mutations.