Universität zu Köln

Marko, Hannah L., Hornig, Nadine C., Betz, Regina C., Holterhus, Paul-Martin, Altmueller, Janine, Thiele, Holger, Fabiano, Marietta ORCID: 0000-0002-4360-6809, Schweikert, Hans-Udo, Braun, Doreen and Schweizer, Ulrich ORCID: 0000-0003-1380-4780 (2022). Genomic variants reducing expression of two endocytic receptors in 46,XY differences of sex development. Hum. Mutat., 43 (3). S. 420 - 434. HOBOKEN: WILEY. ISSN 1098-1004

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Abstract

Transporter-dependent steroid hormone uptake into target cells was demonstrated in genetically engineered mice and fruit flies. We hypothesized that mutations in such transporters may cause differences in sex development (DSD) in humans. Exome sequencing was performed in 16 genetically unsolved cases of 46,XY DSD selected from an anonymized collection of 708 lines of genital fibroblasts (GF) that were taken from individuals with incomplete virilization. Selection criteria were based on available biochemical characterization of GF compatible with reduced androgen uptake. Two unrelated individuals were identified with mutations in LDL receptor-related protein 2 (LRP2), a gene previously associated with partial sex steroid insensitivity in mice. Like Lrp2(-/-) mice, affected individuals had non-descended testes. Western blots on GF confirmed reduced LRP2 expression, and endocytosis of sex hormone-binding globulin was reduced. In three unrelated individuals, two with undescended testes, mutations in another endocytic receptor gene, limb development membrane protein 1 like (LMBR1L), were detected. Two of these individuals had mutations affecting the same codon. In a transfected cell model, mutated LMBR1L showed reduced cell surface expression. Our findings suggest that endocytic androgen uptake in complex with sex hormone-binding globulin is relevant in human. LMBR1L may play a similar role in androgen uptake.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Marko, Hannah L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hornig, Nadine C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Betz, Regina C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Holterhus, Paul-Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Fabiano, Marietta UNSPECIFIED orcid.org/0000-0002-4360-6809 UNSPECIFIED Schweikert, Hans-Udo UNSPECIFIED UNSPECIFIED UNSPECIFIED Braun, Doreen UNSPECIFIED UNSPECIFIED UNSPECIFIED Schweizer, Ulrich UNSPECIFIED orcid.org/0000-0003-1380-4780 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-675905
DOI:	10.1002/humu.24325
Journal or Publication Title:	Hum. Mutat.
Volume:	43
Number:	3
Page Range:	S. 420 - 434
Date:	2022
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1098-1004
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MEMBRANE-RECEPTOR; CELLULAR UPTAKE; TRANSPORTER; MUTATIONS; PREDICTION; RETINOL; MEGALIN; CLONING; ENTRY Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67590