Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Vodopiutz, Julia, Steurer, Lisa-Maria, Haufler, Florentina, Laccone, Franco, Garczarczyk-Asim, Dorota, Hilkenmeier, Matthias, Steinbauer, Philipp, Janecke, Andreas R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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
_version_ 1785032608498843648
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
work_keys_str_mv AT vodopiutzjulia leriweilldyschondrosteosiscausedbyaleakyhomozygousshoxsplicesitevariant
AT steurerlisamaria leriweilldyschondrosteosiscausedbyaleakyhomozygousshoxsplicesitevariant
AT hauflerflorentina leriweilldyschondrosteosiscausedbyaleakyhomozygousshoxsplicesitevariant
AT lacconefranco leriweilldyschondrosteosiscausedbyaleakyhomozygousshoxsplicesitevariant
AT garczarczykasimdorota leriweilldyschondrosteosiscausedbyaleakyhomozygousshoxsplicesitevariant
AT hilkenmeiermatthias leriweilldyschondrosteosiscausedbyaleakyhomozygousshoxsplicesitevariant
AT steinbauerphilipp leriweilldyschondrosteosiscausedbyaleakyhomozygousshoxsplicesitevariant
AT janeckeandreasr leriweilldyschondrosteosiscausedbyaleakyhomozygousshoxsplicesitevariant