2018
DOI: 10.1002/humu.23664
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In vitrofunctional characterization of the novelDHHmutations p.(Asn337Lysfs*24) and p.(Glu212Lys) associated with gonadal dysgenesis

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 cleav… Show more

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Cited by 13 publications
(14 citation statements)
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“…Indeed, like us, Pettigrew et al found that DHH expressed in HEK 293 t cells was mostly uncleaved and yet it was still able to function in juxtacrine signalling. Tajouri et al suggest that DHH autoprocessing is necessary to mediate signalling from Sertoli cells to promote differentiation of the Leydig cells 16. While this may be the case in vivo, our cell culture experiments show that while DHH expressed in this system is mostly uncleaved, variants that lie within the C-terminal domain can still have a significant effect on signalling activation in TM3 mouse Leydig cells.…”
Section: Discussionmentioning
confidence: 47%
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“…Indeed, like us, Pettigrew et al found that DHH expressed in HEK 293 t cells was mostly uncleaved and yet it was still able to function in juxtacrine signalling. Tajouri et al suggest that DHH autoprocessing is necessary to mediate signalling from Sertoli cells to promote differentiation of the Leydig cells 16. While this may be the case in vivo, our cell culture experiments show that while DHH expressed in this system is mostly uncleaved, variants that lie within the C-terminal domain can still have a significant effect on signalling activation in TM3 mouse Leydig cells.…”
Section: Discussionmentioning
confidence: 47%
“…While none of our patients reported any signs of peripheral neuropathy, in several cases the genetic diagnosis prompted clinicians to test for this, and continued monitoring will now be carried out. Tajouri et al hypothesised that C-terminal variants affecting autoprocessing are more likely to lead to gonadal dysgenesis without neuropathies, as even unprocessed DHH protein may induce peripheral nerve development 16. Interestingly though, our patient with a homozygous variant in the N-terminal (patient 1; p.Arg164Pro) which showed a complete LOF has not reported neuropathies.…”
Section: Discussionmentioning
confidence: 62%
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“…Our searches were based on combinations of the following index terms: DHH , 46, XY gonadal dysplasia, 46, XY gonadal dysgenesis, 46, XY disorder of sex development, neuropathy, Hedgehog signaling pathway and the corresponding terms in Chinese. A total of 25 cases of DHH variants causing 46, XY GD in detail have been reported worldwide so far ( Umehara et al, 2000 ; Canto et al, 2004 ; Das et al, 2011 ; Werner et al, 2015 ; Paris et al, 2017 ; Sato et al, 2017 ; Baldinotti et al, 2018 ; Rothacker et al, 2018 ; Tajouri et al, 2018 ; Ayers et al, 2019 ; Buonocore et al, 2019 ; Neocleous et al, 2019 ; Akter et al, 2021 ; Kalinchenko et al, 2021 ; Mehta et al, 2021 ) (see Table 2 ), including 24 different variant types of missense, deletion, duplication, or transversion, and both homozygous and compound heterozygous variants have been reported. The reported ages ranged from 2.8 to 55 years.…”
Section: Case Presentationmentioning
confidence: 99%
“…In the fly, somatic gonadal cells can coalesce into a gonad in the absence of PGCs, but the PGCs are unable to coalesce in the absence of somatic cells (Brookman et al , 1992). Similarly, subsets of somatic gonadal cells produce steroid hormones (testosterone in mammals (Zirkin & Papadopoulos, 2018) and ecdysone in insects (Tajouri et al , 2018)), which have a global influence on the organism.…”
Section: Introductionmentioning
confidence: 99%