The Desert Hedgehog Signalling Pathway in Human Gonadal Development and Differences of Sex Development

While the Hedgehog signalling pathway is implicated in numerous developmental processes and maladies, variants in the Desert Hedgehog (DHH) ligand underlie a condition characterised by 46,XY gonadal dysgenesis with or without peripheral neuropathy. We discuss here the role and regulation of DHH and its signalling pathway in the developing gonads and examine the current understanding of how disruption to this pathway causes this difference of sex development (DSD) in humans.

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Novel Familial Variant of the Desert Hedgehog Gene: Clinical Findings in Two Sisters with 46,XY Gonadal Dysgenesis or 46,XX Karyotype and Literature Review

Hormone Research in Paediatrics ◽

10.1159/000485507 ◽

2018 ◽

Vol 89 (3) ◽

pp. 141-149 ◽

Cited By ~ 7

Author(s):

Fulvia Baldinotti ◽

Tiziana Cavallaro ◽

Eleonora Dati ◽

Giampiero I. Baroncelli ◽

Veronica Bertini ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Gonadal Dysgenesis ◽

Gene Mutations ◽

Premature Termination Codon ◽

Gonadal Development ◽

Comparative Genomic ◽

Exon 2 ◽

Xy Gonadal Dysgenesis ◽

Desert Hedgehog ◽

Clinical Records

Background: In humans, Desert Hedgehog (DHH) gene mutations are a very rare cause of 46,XY gonadal dysgenesis (GD), eventually associated with peripheral neuropathy. Patients and Methods: Clinical records of 12 patients with 46,XY GD and unknown genetic background were reviewed and a 46,XY woman with peripheral neuropathy was individuated. Her 46,XX sister affected by similar neuropathy was also investigated. Genomic DNA was extracted and DHH exons sequenced and analyzed. A comparative genomic hybridization array was also performed. Results: In both the 46,XY and 46,XX sisters, a homozygous c.554C>A mutation in exon 2 of the DHH gene was found, determining a premature termination codon (p.Ser 185*). Heterozygous consanguineous carrier parents showed neither reproductive problems nor peripheral neuropathy. In the proband and her sister, a 499-kb duplication in 9p22.1 was also found. Conclusion: A 46,XY European woman with 46,XY GD and a novel homozygous DHH pathogenic variant is reported, confirming that this gene plays a key role in male gonadal development. Her 46,XX sister, harboring the same mutation, showed normal internal and external female phenotype. Thus, DHH seems not to be involved in the ovarian development pathway or its postpubertal function. Homozygous DHH mutations cause a specific peripheral neuropathy in humans with both 46,XY and 46,XX karyotypes.

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Faculty Opinions recommendation of Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1001713.9107 ◽

2001 ◽

Author(s):

Siew-Lan Ang

Keyword(s):

Sonic Hedgehog ◽

Signalling Pathway ◽

Negative Regulator ◽

Hedgehog Signalling ◽

Hedgehog Signalling Pathway ◽

Sonic Hedgehog Signalling

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Small molecule Hedgehog pathway antagonists

Organic & Biomolecular Chemistry ◽

10.1039/c6ob01959e ◽

2017 ◽

Vol 15 (14) ◽

pp. 3046-3059 ◽

Cited By ~ 2

Author(s):

Trieu N. Trinh ◽

Eileen A. McLaughlin ◽

Christopher P. Gordon ◽

Ilana R. Bernstein ◽

Victoria J. Pye ◽

...

Keyword(s):

Small Molecule ◽

Signalling Pathway ◽

Hedgehog Pathway ◽

Hedgehog Signalling ◽

Hedgehog Signalling Pathway ◽

Ethyl Amine

Leveraging our quinolone-1-(2H)-one based Hedgehog signalling pathway (HSP) inhibitors we have developed two new classes of HSP inhibitors based on: l-tryptophan and benzo[1,3]dioxol-5-ylmethyl-[2-(1H-indol-3-yl)-ethyl]-amine.

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The role of kinases in the Hedgehog signalling pathway

EMBO Reports ◽

10.1038/embor.2008.38 ◽

2008 ◽

Vol 9 (4) ◽

pp. 330-336 ◽

Cited By ~ 34

Author(s):

Reid A Aikin ◽

Katie L Ayers ◽

Pascal P Thérond

Keyword(s):

Signalling Pathway ◽

Hedgehog Signalling ◽

Hedgehog Signalling Pathway

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The Hedgehog signalling pathway in breast development, carcinogenesis and cancer therapy

Breast Cancer Research ◽

10.1186/bcr3401 ◽

2013 ◽

Vol 15 (2) ◽

Cited By ~ 55

Author(s):

Mun Hui ◽

Aurélie Cazet ◽

Radhika Nair ◽

D Neil Watkins ◽

Sandra A O'Toole ◽

...

Keyword(s):

Cancer Therapy ◽

Signalling Pathway ◽

Breast Development ◽

Hedgehog Signalling ◽

Hedgehog Signalling Pathway

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Functional analysis of novel desert hedgehog gene variants improves the clinical interpretation of genomic data and provides a more accurate diagnosis for patients with 46,XY differences of sex development

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105893 ◽

2019 ◽

Vol 56 (7) ◽

pp. 434-443 ◽

Cited By ~ 3

Author(s):

Katie Ayers ◽

Jocelyn van den Bergen ◽

Gorjana Robevska ◽

Nurin Listyasari ◽

Jamal Raza ◽

...

Keyword(s):

Gonadal Dysgenesis ◽

Disorders Of Sex Development ◽

Culture Method ◽

Significant Loss ◽

Subcellular Localisation ◽

Gene Variants ◽

Gene Variant ◽

Clinical Interpretation ◽

Sex Development ◽

Desert Hedgehog

BackgroundDesert hedgehog (DHH) gene variants are known to cause 46,XY differences/disorders of sex development (DSD). We have identified six patients with 46,XY DSD with seven novel DHH gene variants. Many of these variants were classified as variants of uncertain significance due to their heterozygosity or associated milder phenotype. To assess variant pathogenicity and to refine the spectrum of DSDs associated with this gene, we have carried out the first reported functional testing of DHH gene variant activity.MethodsA cell co-culture method was used to assess DHH variant induction of Hedgehog signalling in cultured Leydig cells. Protein expression and subcellular localisation were also assessed for DHH variants using western blot and immunofluorescence.ResultsOur co-culture method provided a robust read-out of DHH gene variant activity, which correlated closely with patient phenotype severity. While biallelic DHH variants from patients with gonadal dysgenesis showed significant loss of activity, variants found as heterozygous in patients with milder phenotypes had no loss of activity when tested with a wild type allele. Taking these functional results into account improved clinical interpretation.ConclusionOur findings suggest heterozygous DHH gene variants are unlikely to cause DSD, reaffirming that DHH is an autosomal recessive cause of 46,XY gonadal dysgenesis. Functional characterisation of novel DHH variants improves variant interpretation, leading to greater confidence in patient reporting and clinical management.

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