The mutational spectrum of holoprosencephaly-associated changes within the SHH gene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis.

Erich Roessler; Kenia El-Jaick; Christèle Dubourg; Jorge Vélez; Benjamin Solomon; Daniel Pineda-Álvarez; Felicitas Lacbawan; Nan Zhou; Maia Ouspenskaia; Aimée Paulussen; Hubert Smeets; Ute Hehr; Claude Bendavid; Sherri Bale; Sylvie Odent; Véronique David; Maximilian Muenke

doi:10.1002/humu.21090

Journal articles

The mutational spectrum of holoprosencephaly-associated changes within the SHH gene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis.

Erich Roessler ¹ Kenia El-Jaick ¹ Christèle Dubourg ^{2, 3} Jorge Vélez ¹ Benjamin Solomon ¹ Daniel Pineda-Álvarez ¹ Felicitas Lacbawan ¹ Nan Zhou ¹ Maia Ouspenskaia ¹ Aimée Paulussen ⁴ Hubert Smeets ⁴ Ute Hehr ⁵ Claude Bendavid ^{2, 3} Sherri Bale ⁶ Sylvie Odent ^{2, 7} Véronique David ^{2, 3} Maximilian Muenke ^{1, *}

* Corresponding author

1 Cancer Genetics Branch

2 IGDR - Institut de Génétique et Développement de Rennes

3 Service de biologie moléculaire

4 Department of Clinical Genetics

5 Department of Human Genetics

6 GeneDx [Gaithersburg, MD, USA]

7 Service de Génétique Clinique

Abstract : Mutations within either the SHH gene or its related pathway components are the most common, and best understood, pathogenetic changes observed in holoprosencephaly patients; this fact is consistent with the essential functions of this gene during forebrain development and patterning. Here we summarize the nature and types of deleterious sequence alterations among over one hundred distinct mutations in the SHH gene (64 novel mutations) and compare these to over a dozen mutations in disease-related Hedgehog family members IHH and DHH. This combined structural analysis suggests that dysfunction of Hedgehog signaling in human forebrain development can occur through truncations or major structural changes to the signaling domain, SHH-N, as well as due to defects in the processing of the mature ligand from its pre-pro-precursor or defective post-translation bi-lipid modifications with palmitate and cholesterol.

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Journal articles

Domain :

Life Sciences [q-bio] / Development Biology

Life Sciences [q-bio] / Genetics

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https://www.hal.inserm.fr/inserm-00406224
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Submitted on : Tuesday, July 21, 2009 - 4:50:04 PM
Last modification on : Wednesday, October 14, 2020 - 3:55:34 AM

The mutational spectrum of holoprosencephaly-associated changes within the SHH gene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis.

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The mutational spectrum of holoprosencephaly-associated changes within the SHH gene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis.

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