In:
Molecular Genetics & Genomic Medicine, Wiley, Vol. 3, No. 6 ( 2015-11), p. 550-557
Kurzfassung:
SOX 9 haploinsufficiency underlies campomelic dysplasia (CD) with or without testicular dysgenesis. Current understanding of the phenotypic variability and mutation spectrum of SOX 9 abnormalities remains fragmentary. Here, we report three patients with hitherto unreported SOX 9 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 SOX 9 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 SOX 9 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 SOX 9 abnormalities. Furthermore, our data broaden pathogenic SOX 9 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.
Materialart:
Online-Ressource
ISSN:
2324-9269
,
2324-9269
DOI:
10.1002/mgg3.2015.3.issue-6
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2015
ZDB Id:
2734884-2
