In vitro functional characterization of the novel DHH mutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis. Issue 12 (22nd October 2018)

• Record Type: Journal Article
• Authors: Tajouri, Asma; Kharrat, Maher; Hizem, Syrine; Zaghdoudi, Hajer; M'rad, Ridha; Simic‐Schleicher, Gunter; Kaiser, Frank J.; Hiort, Olaf; Werner, Ralf
• Is Part Of: Human mutation. Volume 39:Issue 12(2018)
• Page Start: 2097
• Page End: 2109
• Publication Date: 2018-10-22
• Subjects: 46, XY DSD -- auto‐processing -- Desert hedgehog -- gonadal dysgenesis -- polyneuropathy; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23664
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: In humans, mutations of Desert Hedgehog gene ( DHH ) have been described in patients with 46, XY gonadal dysgenesis (GD), associated or not with polyneuropathy. In this study, we describe two patients diagnosed with GD, both harboring novel DHH compound heterozygous mutations p.[Tyr176*];[Asn337Lysfs*24] and p.[Tyr176*];[Glu212Lys]. To investigate the functional consequences of p.(Asn337Lysfs*24) and p.(Glu212Lys) mutations, located within the C‐terminal part of DHh on auto‐processing, we performed in vitro cleavage assays of these proteins in comparison with Drosophila melanogaster Hedgehog (Hh). We found that p.(Glu212Lys) mutation retained 50% of its activity and led to a partially abolished DHh auto‐processing. In contrast, p.(Asn337Lysfs*24) mutation resulted in a complete absence of auto‐proteolysis. Furthermore, we found a different auto‐processing profile between Drosophila Hh and human DHh, which suggests differences in the processing mechanism between the two species. Review of the literature shows that proven polyneuropathy and GD is associated with complete disruption of DHh‐N, whereas disruption of the DHh auto‐processing is only described with GD. We propose a model that may explain the differences between Schwann and Leydig cell development by autocrine versus paracrine DHh signaling. To our knowledge, this is the first study investigating the effect of DHH mutations on DHh in vitro auto‐processing. Abstract : We describe two patients diagnosed with GD, both harboring novel DHH compound heterozygous mutations p.[Tyr176*];[Asn337Lysfs*24] and p.[Tyr176*];[Glu212Lys]. To investigate the functional consequences of p.(Asn337Lysfs*24) and p.(Glu212Lys) mutations, we performed in vitro cleavage assays of these proteins in comparison to Drosophila melanogaster Hedgehog (Hh). While p.(Glu212Lys) retained 50% of its activity and led to a partially abolished DHh auto‐processing, p.(Asn337Lysfs*24) resulted in a complete absence of auto‐proteolysis. Furthermore, we found a different auto‐processing profile between Drosophila Hh and human DHh.