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A novel class of pseudoautosomal region 1 deletions downstream of SHOX is associated with Léri-Weill dyschondrosteosis

A novel class of pseudoautosomal region 1 deletions downstream of SHOX is associated with Léri-Weill dyschondrosteosis
A novel class of pseudoautosomal region 1 deletions downstream of SHOX is associated with Léri-Weill dyschondrosteosis
Leri-Weill dyschondrosteosis (LWD) is a pseudoautosomal dominant disorder characterized by disproportionate short stature and a characteristic curving of the radius, known as the "Madelung deformity." SHOX mutations resulting in SHOX haploinsufficiency have been found in LWD and in a variable proportion of patients with idiopathic short stature (ISS), whereas homozygous loss of SHOX results in the more severe Langer mesomelic dysplasia (LMD). Defects in SHOX have been identified in ~60% of LWD cases, whereas, in the remaining ~40%, the molecular basis is unknown. This suggests either genetic heterogeneity or the presence of mutations in unanalyzed regions of SHOX, such as the upstream, intragenic, or downstream regulatory sequences. Therefore, the pseudoautosomal region 1 (PAR1) of 80 patients with LWD, in whom SHOX deletions and mutations had been excluded, was screened for deletions by use of a new panel of microsatellite markers. We identified 12 patients with LWD who presented with a novel class of PAR1 deletions that did not include SHOX. The deletions were of variable size and mapped at least approximately ~30-530 kb downstream of SHOX. In our cohort, this type of deletion accounted for 15% of cases. In all cases, the deletions cosegregated with the phenotype. No apparent phenotypic differences were observed between patients with SHOX deletions and those with this new class of PAR1 deletions. Thus, we present here the identification of a second PAR1 region implicated in the etiopathogenesis of LWD. Our findings suggest the presence of distal regulatory elements of SHOX transcription in PAR1 or, alternatively, the existence of an additional locus apparently involved in the control of skeletal development. Deletion analysis of this newly identified region should be included in the mutation screening of patients with LWD, LMD, and ISS.
0002-9297
533-544
Benito-Sanz, Sara
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Thomas, N. Simon
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Huber, Céline
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del Blanco, Darya Gorbenko
7a31f2b5-46ac-44f4-959c-bd9b6515c74c
Aza-Carmona, Miriam
b79005a2-d546-4948-8ebd-6a2595f990e8
Crolla, John A.
c5f23751-8de9-4a55-9cc5-ca2fb635769c
Maloney, Vivienne
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Argente, Jesús
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Campos-Barros, Ángel
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Cormier-Daire, Valérie
f7fc91b1-7c48-4729-aa14-cda1ce347340
Heath, Karen E.
2b518a4d-602e-48d0-a91f-22c528d7b330
Benito-Sanz, Sara
1e49d7fa-a683-4ea4-aade-f67593329f13
Thomas, N. Simon
1a601957-288d-4f12-a9f7-4f4279b7f9b3
Huber, Céline
9c1f8a6d-838d-4023-9ba3-0678eee1fbea
del Blanco, Darya Gorbenko
7a31f2b5-46ac-44f4-959c-bd9b6515c74c
Aza-Carmona, Miriam
b79005a2-d546-4948-8ebd-6a2595f990e8
Crolla, John A.
c5f23751-8de9-4a55-9cc5-ca2fb635769c
Maloney, Vivienne
6bf116f3-cb11-4bbf-ac61-888bd3b61a7b
Argente, Jesús
f1e6f200-5ea1-431c-8e01-fc215581ea98
Campos-Barros, Ángel
10b86e44-863e-4a7b-af75-6582761d430c
Cormier-Daire, Valérie
f7fc91b1-7c48-4729-aa14-cda1ce347340
Heath, Karen E.
2b518a4d-602e-48d0-a91f-22c528d7b330

Benito-Sanz, Sara, Thomas, N. Simon, Huber, Céline, del Blanco, Darya Gorbenko, Aza-Carmona, Miriam, Crolla, John A., Maloney, Vivienne, Argente, Jesús, Campos-Barros, Ángel, Cormier-Daire, Valérie and Heath, Karen E. (2005) A novel class of pseudoautosomal region 1 deletions downstream of SHOX is associated with Léri-Weill dyschondrosteosis. The American Journal of Human Genetics, 77 (4), 533-544. (doi:10.1086/449313).

Record type: Article

Abstract

Leri-Weill dyschondrosteosis (LWD) is a pseudoautosomal dominant disorder characterized by disproportionate short stature and a characteristic curving of the radius, known as the "Madelung deformity." SHOX mutations resulting in SHOX haploinsufficiency have been found in LWD and in a variable proportion of patients with idiopathic short stature (ISS), whereas homozygous loss of SHOX results in the more severe Langer mesomelic dysplasia (LMD). Defects in SHOX have been identified in ~60% of LWD cases, whereas, in the remaining ~40%, the molecular basis is unknown. This suggests either genetic heterogeneity or the presence of mutations in unanalyzed regions of SHOX, such as the upstream, intragenic, or downstream regulatory sequences. Therefore, the pseudoautosomal region 1 (PAR1) of 80 patients with LWD, in whom SHOX deletions and mutations had been excluded, was screened for deletions by use of a new panel of microsatellite markers. We identified 12 patients with LWD who presented with a novel class of PAR1 deletions that did not include SHOX. The deletions were of variable size and mapped at least approximately ~30-530 kb downstream of SHOX. In our cohort, this type of deletion accounted for 15% of cases. In all cases, the deletions cosegregated with the phenotype. No apparent phenotypic differences were observed between patients with SHOX deletions and those with this new class of PAR1 deletions. Thus, we present here the identification of a second PAR1 region implicated in the etiopathogenesis of LWD. Our findings suggest the presence of distal regulatory elements of SHOX transcription in PAR1 or, alternatively, the existence of an additional locus apparently involved in the control of skeletal development. Deletion analysis of this newly identified region should be included in the mutation screening of patients with LWD, LMD, and ISS.

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Published date: October 2005

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Local EPrints ID: 44328
URI: https://eprints.soton.ac.uk/id/eprint/44328
ISSN: 0002-9297
PURE UUID: 3d42f73d-57c6-48c9-bcda-6639f412f2c7

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Date deposited: 26 Feb 2007
Last modified: 13 Mar 2019 21:07

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Contributors

Author: Sara Benito-Sanz
Author: N. Simon Thomas
Author: Céline Huber
Author: Darya Gorbenko del Blanco
Author: Miriam Aza-Carmona
Author: John A. Crolla
Author: Vivienne Maloney
Author: Jesús Argente
Author: Ángel Campos-Barros
Author: Valérie Cormier-Daire
Author: Karen E. Heath

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