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In vitrofunctional characterization of the novelDHHmutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis
- Source :
- Human Mutation. 39:2097-2109
- Publication Year :
- 2018
- Publisher :
- Hindawi Limited, 2018.
-
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.
- Subjects :
- Male
0301 basic medicine
Heterozygote
Gonadal dysgenesis
Compound heterozygosity
XY gonadal dysgenesis
Young Adult
03 medical and health sciences
Paracrine signalling
0302 clinical medicine
Protein Domains
Species Specificity
Genetics
medicine
Animals
Drosophila Proteins
Humans
Genetic Predisposition to Disease
Hedgehog Proteins
Autocrine signalling
Hedgehog
Genetic Association Studies
Genetics (clinical)
Desert hedgehog
Gonadal Dysgenesis, 46,XY
biology
biology.organism_classification
medicine.disease
Cell biology
Drosophila melanogaster
030104 developmental biology
Child, Preschool
Mutation
Proteolysis
Female
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 10597794
- Volume :
- 39
- Database :
- OpenAIRE
- Journal :
- Human Mutation
- Accession number :
- edsair.doi.dedup.....fac5659fa985e452d2bc9e4cbba4e7c9