Identification of novel genes involved in sexual development is crucial for understanding disorders of sex development (DSD). Here, we propose a member of the START domain family, the X chromosome STARD8, as a DSD candidate gene. We have identified a missense mutation of this gene in 2 sisters with 46,XY gonadal dysgenesis, inherited from their heterozygous mother. Gonadal tissue of one of the sisters contained Leydig cells overloaded with cholesterol droplets, i.e., structures previously identified in 46,XY DSD patients carrying mutations in the STAR gene encoding another START domain family member, which is crucial for steroidogenesis. Based on the phenotypes of our patients, we propose a dual role of STARD8 in sexual development, namely in testes determination and testosterone synthesis. However, further studies are needed to confirm the involvement of STARD8 in sexual development.

Keywords:
STAR, STARD8, Testosterone synthesis, Disorders of sexual development
1.
Bhangoo A, Gu WX, Pavlakis S, Anhalt H, Heier L, et al: Phenotypic features associated with mutations in steroidogenic acute regulatory protein. J Clin Endocrinol Metab 90:6303-6309 (2005).
2.
Bose HS, Sugawara T, Strauss JF, 3rd, Miller WL, International Congenital Lipoid Adrenal Hyperplasia C: The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med 335:1870-1878 (1996).
3.
Callier P, Calvel P, Matevossian A, Makrythanasis P, Bernard P, et al: Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling. PLoS Genet 10: e1004340 (2014).
4.
Clark BJ: The mammalian START domain protein family in lipid transport in health and disease. J Endocrinol 212:257-275 (2012).
5.
Clark BJ, Wells J, King SR, Stocco DM: The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 269:28314-28322 (1994).
6.
Domenice S, Machado AZ, Ferreira FM, Ferraz-de-Souza B, Lerario AM, et al: Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals. Birth Defects Res C Embryo Today 108:309-320 (2016).
7.
Eggers S, Sadedin S, van den Bergen JA, Robevska G, Ohnesorg T, et al: Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biol 17:243 (2016).
8.
Jameson SA, Natarajan A, Cool J, DeFalco T, Maatouk DM, et al: Temporal transcriptional profiling of somatic and germ cells reveals biased lineage priming of sexual fate in the fetal mouse gonad. PLoS Genet 8:e1002575 (2012).
9.
Khoury K, Barbar E, Ainmelk Y, Ouellet A, Lavigne P, LeHoux JG: Thirty-eight-year follow-up of two sibling lipoid congenital adrenal hyperplasia patients due to homozygous steroidogenic acute regulatory (STARD1) protein mutation. Molecular structure and modeling of the STARD1 L275P mutation. Front Neurosci 10:527 (2016).
10.
Lin D, Sugawara T, Strauss JF, 3rd, Clark BJ, Stocco DM, et al: Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 267:1828-1831 (1995).
11.
McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, et al: The Ensembl variant effect predictor. Genome Biol 17:122 (2016).
12.
Nef S, Sachaad O, Stallings NR, Cederroth CR, Pitetti JL, et al: Gene expression during sex determination reveals a robust female genetic program at the onset of ovarian development. Dev Biol 287:361-377 (2005).
13.
Santoni FA, Makrythanasis P, Nikolaev S, Guipponi M, Robyr D, et al: Simultaneous identification and prioritization of variants in familial, de novo, and somatic genetic disorders with VariantMaster. Genome Res 24:349-355 (2014).
14.
Sugawara T, Holt JA, Driscoll D, Strauss JF, 3rd, Lin D, et al: Human steroidogenic acute regulatory protein: functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13. Proc Natl Acad Sci USA 92:4778-4782 (1995).
15.
Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, et al: Proteomics. Tissue-based map of the human proteome. Science 347:1260419 (2015).
© 2018 S. Karger AG, Basel
2018
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.