ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 6.3 | DOI: 10.1530/ey.18.6.3

Int J Mol Sci. 2020 Nov 9;21(21):8403. doi: 10.3390/ijms21218403. PMID: 33182400

This case report describes a patient with clinically diagnosed partial androgen insensitivity syndrome (PAIS). However, no mutation in the androgen receptor gene was identified. Instead, whole genome sequencing revealed a heterozygous point mutation inherited from the mother in the FKBP4 gene. This gene is a positive modulator of AR gene transcription. The mutation was located in one of the three repeats (TPR) responsible for the interaction with several proteins essential for upregulation of AR transcription and thus activity.

A corresponding gene in mice has been shown to cause genital anomalies in homozygous but not in heterozygous loss-of-function mutations. The authors speculate that the gene may be subject to imprinting in humans, as an explanation for the discrepancy. It has been postulated since some time that deficiencies related to androgen receptor (AR) cofactors or translation of the AR gene would be involved in AIS (1). This is the first time that a mutation in a regulatory gene of the androgen signalling pathway is identified in humans.

A recently published thorough review on androgen insensitivity describes the intricate molecular system and factors involved in the transportation and activation of the androgen receptor (1). Mutations in the AR gene are detected in < 25% of cases with a clinical PAIS phenotype and the phenotype/genotype correlation is especially variable in PAIS, even when a mutation is identified. The androgen-regulated endogenous AR-target gene in genital skin fibroblasts, Apolipoprotein D (APOD) has enabled the development of an assay using this gene as a biomarker of androgen signalling at the cellular level, even in absence of an AR mutation. This has been defined AIS type II and further stimulated the search for unidentified cofactors responsible for PAIS. (1). The paper by Ilaslan is the first one to identify such a possible genetic link, and the APOD assay as proposed by Hornig et al. could serve as an optimal in vitro model to test the functional effect of this and other newly identified genetic variants.

Reference: 1. Hornig NC, Holterhus PM. Molecular basis of androgen insensitivity syndromes. Mol Cell Endocrinol. 2021 Mar 1;523:111146. doi: 10.1016/j.mce.2020.111146. PMID: 33385475

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