• PMID: 29264534
• Gene Name: AR
• Condition: PAIS with infertility associated with azoospermia, hypospadias, and gynecomastia
• Association: Associated
• Mutation: g.66788676A>C, c.1616+22072A>C, stop codon at chrX:66863131-66863133
• Population size: 4
• Population details: 4 cases
• Sex: Male
• Infertility type: Male infertility

Identification of the Underlying Androgen Receptor Defect in the Dallas Reifenstein Family

Ahmad Z, Xing C, Panach K, Kittler R, McPhaul MJ, Wilson JD.

CONTEXT: The Dallas Reifenstein family - first described in 1965 - includes 14 known members with partial androgen insensitivity syndrome (PAIS). However, the underlying molecular defect was never identified. OBJECTIVE: To identify the underlying genetic defect for PAIS in the Dallas Reifenstein family. DESIGN: DNA was purified from scrotal skin fibroblasts, and whole exome sequencing was then performed in four affected men in the family. Additional family members - both affected and unaffected - were subsequently recruited to confirm segregation of the candidate mutations with the PAIS phenotype. PATIENTS: The affected men have PAIS with infertility associated with azoospermia, hypospadias, and gynecomastia. RESULTS: All four men harbored an intronic variant NC_000023.10:g.66788676A>C between exon 1 and exon 2 of the androgen receptor (AR) canonical transcript NM_000044 (complementary DNA position NM_000044: c.1616+22072A>C) predicted to cause an alternatively spliced AR transcript. Reverse transcription (RT) polymerase chain (PCR) experiments detected the predicted PCR product of the alternatively spliced AR transcript, and the mutation segregated with the PAIS phenotype in this family. The transcript includes the insertion of 185 nucleotides with a premature stop codon at chrX:66863131-66863133, likely resulting in a reduction in AR protein expression due to nonsense-mediated decay. CONCLUSIONS: An intronic AR mutation was identified in the Dallas Reifenstein family. The findings suggest that in cases of PAIS without identifiable AR mutations in coding regions, intronic AR mutations should be considered. FAU - Ahmad, Zahid AU - Ahmad Z AD - Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, UT Southwestern Medical Center, Dallas, Texas 75390. FAU - Xing, Chao AU - Xing C AD - McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas 75390. FAU - Panach, Kamaldeep AU - Panach K AD - Division of Endocrinology and Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas 75390. FAU - Kittler, Ralf AU - Kittler R AD - McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas 75390. FAU - McPhaul, Michael J AU - McPhaul MJ AD - Division of Endocrinology and Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas 75390. AD - Quest Diagnostics Nichols Institute, San Juan Capistrano, California 92665.