Koopmann, TT;
Jamshidi, Y;
Naghibi-Sistani, M;
van der Klift, HM;
Birjandi, H;
Al-Hassnan, Z;
Alwadai, A;
Zifarelli, G;
Karimiani, EG;
Sedighzadeh, S;
et al.
Koopmann, TT; Jamshidi, Y; Naghibi-Sistani, M; van der Klift, HM; Birjandi, H; Al-Hassnan, Z; Alwadai, A; Zifarelli, G; Karimiani, EG; Sedighzadeh, S; Bahreini, A; Nouri, N; Peter, M; Watanabe, K; van Duyvenvoorde, HA; Ruivenkamp, CAL; Teunissen, AKK; Ten Harkel, ADJ; van Duinen, SG; Haak, MC; Prada, CE; Santen, GWE; Maroofian, R
(2023)
Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy.
Eur J Hum Genet, 31 (1).
pp. 97-104.
ISSN 1476-5438
https://doi.org/10.1038/s41431-022-01204-9
SGUL Authors: Jamshidi, Yalda
Abstract
Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism.
Item Type: |
Article
|
Additional Information: |
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
© The Author(s) 2022 |
Keywords: |
0604 Genetics, 1103 Clinical Sciences, Genetics & Heredity |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: |
Eur J Hum Genet |
ISSN: |
1476-5438 |
Language: |
eng |
Dates: |
Date | Event |
---|
January 2023 | Published | 17 October 2022 | Published Online | 23 September 2022 | Accepted |
|
Publisher License: |
Creative Commons: Attribution 4.0 |
PubMed ID: |
36253531 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/114929 |
Publisher's version: |
https://doi.org/10.1038/s41431-022-01204-9 |
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