ESPE Yearbook of Paediatric Endocrinology

Brief summary: This translational study highlights the importance of 2 novel endocytic receptors that are involved in cellular androgen uptake and in the pathogenesis of androgen insensitivity syndrome (AIS) type II.

Steroids circulate in complex with plasma transfer proteins, and specific endocytic receptors can mediate cellular uptake of transfer protein/ligand complexes. Reduced intracellular hormone concentrations resulting from impaired hormone uptake might underlie reduced androgen-mediated gene expression. Therefore, some genetic defects which are associated with cellular androgen uptake may explain the etiology of DSD, especially in individuals with clinical AIS without an AR mutation (AIS Type II).

In this study, Marko HL et al., identified pathogenic variants in two genes encoding two endocytic receptors namely LDL receptor related protein 2 (LRP2) and limb development membrane protein 1 like (LMBR1L) genes, in individuals with AIS type II. Besides clinical PAIS phenotype, genital skin fibroblasts obtained from these individuals showed reduced cell membrane expression of these receptors and reduced AR activity.

The androgens circulate with sex hormone-binding globulin (SHBG) in plasma. In mice, LRP2 acts as an endocytic receptor for the SHBG/androgen complex to transmit the signal to the androgen receptor in the cytoplasm of specific hormone target cells. LRP2 is known to mediate testosterone-dependent testicular descend in mice which is similar in individuals with LRP2 mutations. This study showed that endocytosis of SHBG conjugated to a fluorescent dye is reduced in genital skin fibroblasts from 2 individuals with AIS type II carrying mutations in LRP2. Furthermore, mutations were identified in the lipocalin receptor gene, LMBR1L, in 3 patients with AIS type II. LMBR1L knockout cell line which were transiently transfected with expression vectors encoding LMBR1L wildtype as well as LMBR1L variants showed reduced cell surface expression of the receptor by 65–75%. Reduced androgen receptor activity related to LRP2 and LMBR1L mutations was shown by reduced androgen-responsive APOD gene mRNA expression in genital skin fibroblasts after incubation with dihydrotestosterone.

Although a few patients were described with these mutations, this study illustrates impaired cellular androgen uptake in the pathogenesis of androgen insensitivity syndrome type II. The molecular etiology in the majority of the patients with androgen insensitivity syndrome type II is yet to be identified.