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Leri–Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant
SHOX deficiency is a common genetic cause of short stature of variable degree. SHOX haploinsufficiency causes Leri–Weill dyschondrosteosis (LWD) as well as nonspecific short stature. SHOX haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138022/ https://www.ncbi.nlm.nih.gov/pubmed/37107635 http://dx.doi.org/10.3390/genes14040877 |
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author | Vodopiutz, Julia Steurer, Lisa-Maria Haufler, Florentina Laccone, Franco Garczarczyk-Asim, Dorota Hilkenmeier, Matthias Steinbauer, Philipp Janecke, Andreas R. |
author_facet | Vodopiutz, Julia Steurer, Lisa-Maria Haufler, Florentina Laccone, Franco Garczarczyk-Asim, Dorota Hilkenmeier, Matthias Steinbauer, Philipp Janecke, Andreas R. |
author_sort | Vodopiutz, Julia |
collection | PubMed |
description | SHOX deficiency is a common genetic cause of short stature of variable degree. SHOX haploinsufficiency causes Leri–Weill dyschondrosteosis (LWD) as well as nonspecific short stature. SHOX haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant inheritance, while biallelic SHOX loss-of-function variants cause the more severe skeletal dysplasia, Langer mesomelic dyschondrosteosis (LMD). Here we report for the first time the pseudo-autosomal recessive inheritance of LWD in two siblings caused by a novel homozygous non-canonical, leaky splice-site variant in intron 3 of SHOX: c.544+5G>C. Transcript analyses in patient-derived fibroblasts showed homozygous patients to produce approximately equal amounts of normally spliced mRNA and mRNA with the abnormal retention of intron 3 and containing a premature stop codon (p.Val183Glyfs*31). The aberrant transcript was shown to undergo nonsense-mediated mRNA decay, and thus resulting in SHOX haploinsufficiency in the homozygous patient. Six healthy relatives who are of normal height are heterozygous for this variant and fibroblasts from a heterozygote for the c.544+5G>C variant produced wild-type transcript amounts comparable to healthy control. The unique situation reported here highlights the fact that the dosage of SHOX determines the clinical phenotype rather than the Mendelian inheritance pattern of SHOX variants. This study extends the molecular and inheritance spectrum of SHOX deficiency disorder and highlights the importance of functional testing of SHOX variants of unknown significance in order to allow appropriate counseling and precision medicine for each family individual. |
format | Online Article Text |
id | pubmed-10138022 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-101380222023-04-28 Leri–Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant Vodopiutz, Julia Steurer, Lisa-Maria Haufler, Florentina Laccone, Franco Garczarczyk-Asim, Dorota Hilkenmeier, Matthias Steinbauer, Philipp Janecke, Andreas R. Genes (Basel) Article SHOX deficiency is a common genetic cause of short stature of variable degree. SHOX haploinsufficiency causes Leri–Weill dyschondrosteosis (LWD) as well as nonspecific short stature. SHOX haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant inheritance, while biallelic SHOX loss-of-function variants cause the more severe skeletal dysplasia, Langer mesomelic dyschondrosteosis (LMD). Here we report for the first time the pseudo-autosomal recessive inheritance of LWD in two siblings caused by a novel homozygous non-canonical, leaky splice-site variant in intron 3 of SHOX: c.544+5G>C. Transcript analyses in patient-derived fibroblasts showed homozygous patients to produce approximately equal amounts of normally spliced mRNA and mRNA with the abnormal retention of intron 3 and containing a premature stop codon (p.Val183Glyfs*31). The aberrant transcript was shown to undergo nonsense-mediated mRNA decay, and thus resulting in SHOX haploinsufficiency in the homozygous patient. Six healthy relatives who are of normal height are heterozygous for this variant and fibroblasts from a heterozygote for the c.544+5G>C variant produced wild-type transcript amounts comparable to healthy control. The unique situation reported here highlights the fact that the dosage of SHOX determines the clinical phenotype rather than the Mendelian inheritance pattern of SHOX variants. This study extends the molecular and inheritance spectrum of SHOX deficiency disorder and highlights the importance of functional testing of SHOX variants of unknown significance in order to allow appropriate counseling and precision medicine for each family individual. MDPI 2023-04-07 /pmc/articles/PMC10138022/ /pubmed/37107635 http://dx.doi.org/10.3390/genes14040877 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Vodopiutz, Julia Steurer, Lisa-Maria Haufler, Florentina Laccone, Franco Garczarczyk-Asim, Dorota Hilkenmeier, Matthias Steinbauer, Philipp Janecke, Andreas R. Leri–Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant |
title | Leri–Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant |
title_full | Leri–Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant |
title_fullStr | Leri–Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant |
title_full_unstemmed | Leri–Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant |
title_short | Leri–Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant |
title_sort | leri–weill dyschondrosteosis caused by a leaky homozygous shox splice-site variant |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138022/ https://www.ncbi.nlm.nih.gov/pubmed/37107635 http://dx.doi.org/10.3390/genes14040877 |
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