Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9

Abstract

SOX9 haploinsufficiency underlies campomelic dysplasia (CD) with or without testicular dysgenesis. Current understanding of the phenotypic variability and mutation spectrum of SOX9 abnormalities remains fragmentary. Here, we report three patients with hitherto unreported SOX9 abnormalities. These patients were identified through molecular analysis of 33 patients with 46,XY disorders of sex development (DSD). Patients 1–3 manifested testicular dysgenesis or regression without CD. Patients 1 and 2 carried probable damaging mutations p.Arg394Gly and p.Arg437Cys, respectively, in the SOX9 C‐terminal domain but not in other known 46,XY DSD causative genes. These substitutions were absent from ~120,000 alleles in the exome database. These mutations retained normal transactivating activity for the Col2a1 enhancer, but showed impaired activity for the Amh promoter. Patient 3 harbored a maternally inherited ~491 kb SOX9 upstream deletion that encompassed the known 32.5 kb XY sex reversal region. Breakpoints of the deletion resided within nonrepeat sequences and were accompanied by a short‐nucleotide insertion. The results imply that testicular dysgenesis and regression without skeletal dysplasia may be rare manifestations of SOX9 abnormalities. Furthermore, our data broaden pathogenic SOX9 abnormalities to include C‐terminal missense substitutions which lead to target‐gene‐specific protein dysfunction, and enhancer‐containing upstream microdeletions mediated by nonhomologous end‐joining.

Newly Identified t(2;17)(p15;q24.2) Chromosomal Translocation Is Associated with Dysgenetic Gonads and Multiple Somatic Anomalies

“…The enhancer region exists in up to 2.0 Mb upstream of SOX9, and the chromosome translocation that results in CD or ACD exists at 50-375 kb, 379-459 kb, 585-932 kb, and 1.02-1.20 Mb upstream of SOX9. These are all a part of the locus 17q24.3 (Gordon et al 2014;Karaer et al 2014;Kim et al 2015;Katoh-Fukui et al 2015;Castori et al 2016). In the present case, a FISH analysis found that the breakpoint existed at chromosome 17q24.2, which has never been reported with respect to CD (Fig.…”

The SOXE transcription factors—SOX8, SOX9 and SOX10—share a bi-partite transactivation mechanism

“…Missense mutations are almost always located in the HMG domain or SOXE dimerization domain. The only two missense mutations reported in the SOX9 TAC domain (R394G and R437C) caused testicular dysgenesis, but no sex reversal and no campomelic dysplasia, thus a less severe disease than that caused by allele deletions (62). To our knowledge, no missense mutations or in-frame microdeletions causing a developmental disease have been reported for the SOXE TAM domain and for the SOXE/SOXF EΦ[D/E]QYΦ motif.…”

<b><i>NR0B1</i></b> Frameshift Mutation in a Boy with Idiopathic Central Precocious Puberty

“…Sequence data were analyzed as described previously [Katoh-Fukui et al, 2015]. In this study, we focused on 32 genes known to be involved in the regulation of the HPG axis [Izumi et al, 2014;Macedo et al, 2016].…”