Consider CUX1 variants in children with a variation of sex development: a case report and review of the literature.
ADHD
ASD
CUX1
Cryptorchidism
DSD
Disorder of sex development
Gonads
Hypospadias
Testis
VSD
Variation of sex characteristics
Variation of sex development
Journal
BMC medical genomics
ISSN: 1755-8794
Titre abrégé: BMC Med Genomics
Pays: England
ID NLM: 101319628
Informations de publication
Date de publication:
05 Aug 2024
05 Aug 2024
Historique:
received:
04
03
2024
accepted:
21
06
2024
medline:
6
8
2024
pubmed:
6
8
2024
entrez:
5
8
2024
Statut:
epublish
Résumé
The Cut Homeobox 1 (CUX1) gene has been implicated in a number of developmental processes and has recently emerged as an important cause of developmental delay and impaired intellectual development. Individuals with variants in CUX1 have been described with a variety of co-morbidities including variations in sex development (VSD) although these features have not been closely documented. The proband is a 14-year-old male who presented with congenital complex hypospadias, neurodevelopmental differences, and subtle dysmorphism. A family history of neurodevelopmental differences and VSD was noted. Microarray testing and whole exome sequencing found the 46,XY proband had a large heterozygous in-frame deletion of exons 4-10 of the CUX1 gene. Our review of the literature has revealed that variants in CUX1 are associated with a range of VSD and suggest this gene should be considered in cases where a VSD is noted at birth, especially if there is a familial history of VSD and/or neurodevelopmental differences. Further work is required to fully investigate the role and regulation of CUX1 in sex development.
Sections du résumé
BACKGROUND
BACKGROUND
The Cut Homeobox 1 (CUX1) gene has been implicated in a number of developmental processes and has recently emerged as an important cause of developmental delay and impaired intellectual development. Individuals with variants in CUX1 have been described with a variety of co-morbidities including variations in sex development (VSD) although these features have not been closely documented.
CASE PRESENTATION
METHODS
The proband is a 14-year-old male who presented with congenital complex hypospadias, neurodevelopmental differences, and subtle dysmorphism. A family history of neurodevelopmental differences and VSD was noted. Microarray testing and whole exome sequencing found the 46,XY proband had a large heterozygous in-frame deletion of exons 4-10 of the CUX1 gene.
CONCLUSIONS
CONCLUSIONS
Our review of the literature has revealed that variants in CUX1 are associated with a range of VSD and suggest this gene should be considered in cases where a VSD is noted at birth, especially if there is a familial history of VSD and/or neurodevelopmental differences. Further work is required to fully investigate the role and regulation of CUX1 in sex development.
Identifiants
pubmed: 39103808
doi: 10.1186/s12920-024-01945-0
pii: 10.1186/s12920-024-01945-0
doi:
Substances chimiques
Homeodomain Proteins
0
CUX1 protein, human
0
Repressor Proteins
0
Transcription Factors
0
Types de publication
Journal Article
Case Reports
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
195Subventions
Organisme : National Health and Medical Research Council
ID : GNT2025619
Organisme : National Health and Medical Research Council
ID : GNT2012250
Informations de copyright
© 2024. The Author(s).
Références
Jotte MRM, McNerney ME. The significance of CUX1 and chromosome 7 in myeloid malignancies. Curr Opin Hematol. 2022;29(2):92–102.
doi: 10.1097/MOH.0000000000000699
pubmed: 35084368
pmcid: 8795693
Lievens PM, Tufarelli C, Donady JJ, Stagg A, Neufeld EJ. CASP, a novel, highly conserved alternative-splicing product of the CDP/cut/cux gene, lacks cut-repeat and homeo DNA-binding domains, and interacts with full-length CDP in vitro. Gene. 1997;197(1–2):73–81.
doi: 10.1016/S0378-1119(97)00243-6
pubmed: 9332351
Hulea L, Nepveu A. CUX1 transcription factors: from biochemical activities and cell-based assays to mouse models and human diseases. Gene. 2012;497(1):18–26.
doi: 10.1016/j.gene.2012.01.039
pubmed: 22306263
Leyva-Diaz E. CUT homeobox genes: transcriptional regulation of neuronal specification and beyond. Front Cell Neurosci. 2023;17:1233830.
doi: 10.3389/fncel.2023.1233830
pubmed: 37744879
pmcid: 10515288
Weiss LA, Nieto M. The crux of Cux genes in neuronal function and plasticity. Brain Res. 2019;1705:32–42.
doi: 10.1016/j.brainres.2018.02.044
pubmed: 29518378
Platzer K, Cogne B, Hague J, Marcelis CL, Mitter D, Oberndorff K, et al. Haploinsufficiency of CUX1 causes nonsyndromic global developmental delay with possible catch-up development. Ann Neurol. 2018;84(2):200–7.
doi: 10.1002/ana.25278
pubmed: 30014507
Oppermann H, Marcos-Graneda E, Weiss LA, Gurnett CA, Jelsig AM, Vineke SH, et al. CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology. Eur J Hum Genet. 2023;31(11):1251–60.
doi: 10.1038/s41431-023-01445-2
pubmed: 37644171
pmcid: 10620399
Sansregret L, Nepveu A. The multiple roles of CUX1: insights from mouse models and cell-based assays. Gene. 2008;412(1–2):84–94.
doi: 10.1016/j.gene.2008.01.017
pubmed: 18313863
Iulianella A, Vanden Heuvel G, Trainor P. Dynamic expression of murine Cux2 in craniofacial, limb, urogenital and neuronal primordia. Gene Expr Patterns. 2003;3(5):571–7.
doi: 10.1016/S1567-133X(03)00123-6
pubmed: 12971989
Kroll MR, Viss ES, Lamb J, Horstman J, Powell A, Van Wyk A, et al. Asynchronous expression of the homeodomain protein CUX1 in Sertoli cells and spermatids during spermatogenesis in mice. Biol Reprod. 2011;84(3):455–65.
doi: 10.1095/biolreprod.110.084335
pubmed: 20980687
Luong MX, van der Meijden CM, Xing D, Hesselton R, Monuki ES, Jones SN, et al. Genetic ablation of the CDP/Cux protein C terminus results in hair cycle defects and reduced male fertility. Mol Cell Biol. 2002;22(5):1424–37.
doi: 10.1128/MCB.22.5.1424-1437.2002
pubmed: 11839809
pmcid: 134686
Vanden Heuvel GB, Quaggin SE, Igarashi P. A unique variant of a homeobox gene related to Drosophila cut is expressed in mouse testis. Biol Reprod. 1996;55(4):731–9.
doi: 10.1095/biolreprod55.4.731
pubmed: 8879483
Krishnan M, Senagolage MD, Baeten JT, Wolfgeher DJ, Khan S, Kron SJ, et al. Genomic studies controvert the existence of the CUX1 p75 isoform. Sci Rep. 2022;12(1):151.
doi: 10.1038/s41598-021-03930-4
pubmed: 34997000
pmcid: 8741762
Mueller JK, Dietzel A, Lomniczi A, Loche A, Tefs K, Kiess W, et al. Transcriptional regulation of the human KiSS1 gene. Mol Cell Endocrinol. 2011;342(1–2):8–19.
doi: 10.1016/j.mce.2011.04.025
pubmed: 21672609
pmcid: 3148268
Hetu V, Caron E, Francoeur D. Hypoplastic uterus and clitoris enlargement in Swyer syndrome. J Pediatr Adolesc Gynecol. 2010;23(1):e43–5.
doi: 10.1016/j.jpag.2009.03.004
pubmed: 19643642
Berglund A, Johannsen TH, Stochholm K, Viuff MH, Fedder J, Main KM, et al. Incidence, prevalence, diagnostic delay, and clinical presentation of female 46, XY disorders of sex development. J Clin Endocrinol Metab. 2016;101(12):4532–40.
doi: 10.1210/jc.2016-2248
pubmed: 27603905
Garcia-Alonso L, Lorenzi V, Mazzeo CI, Alves-Lopes JP, Roberts K, Sancho-Serra C, et al. Single-cell roadmap of human gonadal development. Nature. 2022;607(7919):540–7.
doi: 10.1038/s41586-022-04918-4
pubmed: 35794482
pmcid: 9300467
Consortium GT. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 2020;369(6509):1318–30.
doi: 10.1126/science.aaz1776