Intragenic Duplication of DMRT1 in a SRY-Negative Boy with 46,XX Disorder of Sex Development

Background. 46,XX disorders of sex development are rare. Approximately, 90% of XX males are SRY-positive, while testicular development in the absence of SRY takes place in a minority. Methods: A boy with 46,XX karyotype (SRY-negative; absence of SOX9 duplications) was investigated by targeted Next Generation Sequencing (NGS), Multiplex ligation-dependent probe amplification (MLPA), and Comparative Genomic Hybridization array (CGH-array). Results: The boy had normal male phenotype and normal prepubertal values of testicular hormones. He presented a heterozygous duplication of 49.626 bp, encompassing exons 2 and 3 of DMRT1. The result was arr[GRCh37] 9p24.3(845893_895518)x3. Since both breakpoints are harbored in the intronic regions, the duplication does not stop or shift the coding frame. Additional known pathogenic or uncertain variants in pro-testis gene cascade were not identified. Conclusions: This study report a boy with 46,XX testicular disorder of sex differentiation, showing a de novo partial intragenic duplication of DMRT1. This intragenic duplication may result in a gain of function, acting as primary pro-testis gene (or anti-ovary gene) in a 46,XX human foetus and permitting normal pre-pubertal endocrine testis function.

7-Transmembrane Helical (7TMH) Proteins: Pseudo-Symmetry and Conformational Plasticity

Membrane proteins sharing 7 transmembrane helices (7-TMH) dominate the polytopic TMH proteome. They cannot be grouped under a monolithic fold or superfold, however, a parallel structural analysis of folds around that magic number of 7-TMH in distinct 6/7/8-TMH protein superfamilies (SWEET, PnuC, TRIC, FocA, Aquaporin, GPCRs, AND MFS), reveals a common homology, not in their structural fold, but in their systematic pseudo-symmetric construction. Our analysis leads to guiding principles of intragenic duplication and pseudo-symmetric assembly of ancestral 3 or 4 Transmembrane Helix (3/4-TMH) protodomains/protofolds. A parallel deconstruction and reconstruction of these domains provides a structural and mechanistic framework for the evolution path of current pseudo-symmetrical transmembrane helical (TMH) proteins. It highlights the conformational plasticity inherent to fold formation itself. The sequence/structure analysis of different 6/7/8-TMH superfamilies provides a unifying theme of their evolutionary process involving the intragenic duplication of protodomains with varying degrees of sequence and fold divergence under conformational and functional constraints.