Mechanism of Disease: Recessive ADAMTSL4 Mutations and Craniosynostosis with Ectopia Lentis

Gustafson, Jonas; Björk, Maria; Ravenswaaij-Arts, Conny M. A. van; Cunningham, Michael L.

doi:10.1155/2022/3239260

Cited by 5 publications

(4 citation statements)

References 51 publications

(60 reference statements)

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“…Additionally, we observed enrichment of possibly relevant variants in genes involved in the TGF-β pathway ( ADAMTSL4, LTBP1 , LTBP4 and TGFBR1 - Supplementary Table S4 ) with a role in the morphogenesis of the skull sutures ( Rawlins and Opperman, 2008 ). Furthermore, CS was recently reported in patients with bi-allelic mutations in ADAMTSL4 and LTBP1 ( Pottie et al, 2021 ; Gustafson et al, 2022 ). Also, we observed enrichment of heterozygous carriers of variants in CS-related autosomal recessive genes from the ciliopathy spectrum (e.g., IFT122 , IFT140 , and WDR19 - Supplementary Table S4 ).…”

Section: Discussionmentioning

confidence: 96%

The value of genome-wide analysis in craniosynostosis

Topa,

Rohlin,

Fehr

et al. 2024

Front. Genet.

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Background: This study assessed the diagnostic yield of high-throughput sequencing methods in a cohort of craniosynostosis (CS) patients not presenting causal variants identified through previous targeted analysis.Methods: Whole-genome or whole-exome sequencing (WGS/WES) was performed in a cohort of 59 patients (from 57 families) assessed by retrospective phenotyping as having syndromic or nonsyndromic CS.Results: A syndromic form was identified in 51% of the unrelated cases. A genetic cause was identified in 38% of syndromic cases, with novel variants detected in FGFR2 (a rare Alu insertion), TWIST1, TCF12, KIAA0586, HDAC9, FOXP1, and NSD2. Additionally, we report two patients with rare recurrent variants in KAT6A and YY1 as well as two patients with structural genomic aberrations: one with a 22q13 duplication and one with a complex rearrangement involving chromosome 2 (2p25 duplication including SOX11 and deletion of 2q22). Moreover, we identified potentially relevant variants in 87% of the remaining families with no previously detected causal variants, including novel variants in ADAMTSL4, ASH1L, ATRX, C2CD3, CHD5, ERF, H4C5, IFT122, IFT140, KDM6B, KMT2D, LTBP1, MAP3K7, NOTCH2, NSD1, SOS1, SPRY1, POLR2A, PRRX1, RECQL4, TAB2, TAOK1, TET3, TGFBR1, TCF20, and ZBTB20.Conclusion: These results confirm WGS/WES as a powerful diagnostic tool capable of either targeted in silico or broad genomic analysis depending on phenotypic presentation (e.g., classical or unusual forms of syndromic CS).

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Section: Discussionmentioning

confidence: 96%

The value of genome-wide analysis in craniosynostosis

Topa,

Rohlin,

Fehr

et al. 2024

Front. Genet.

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“…As for molecular pathogensis, ADAMTSL4 variants have been identified broadly in ELrelated eye disorders, including isolated EL (OMIM 225100) (Ahram et al, 2009;Aragon-Martin et al, 2010;Chandra et al, 2012;Chandra et al, 2013a;Dollfus et al, 2010;Neuhann et al, 2015;Overwater et al, 2017;Reinstein et al, 2016;van Bysterveldt et al, 2017;Guo. Et al., 2022), autosomal recessive ELeP (OMIM 225200) ( Christensen et al, 2010;Sharifi et al, 2013;Overwater et al, 2017;Safi et al, 2019), and EL with craniosynostosis (OMIM 603595) (Chandra et al, 2013a;Gustafson, et al, 2022). About the inheritance manner of ADAMTSL4-related eye disorders, previous studies exhibit major in recessive manner (Ahram et al, 2009;Aragon-Martin et al, 2010;Dollfus et al, 2010;Christensen et al, 2010;Chandra et al, 2012;Reinstein et al, 2016;van Bysterveldt et al, 2017;Gustafson, et al, 2022), and other manners including pseudodominant and dominant styles (Sharifi, et al, 2013;Scanga and Nischal, 2022;Chen TH, et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Et al., 2022), autosomal recessive ELeP (OMIM 225200) ( Christensen et al, 2010;Sharifi et al, 2013;Overwater et al, 2017;Safi et al, 2019), and EL with craniosynostosis (OMIM 603595) (Chandra et al, 2013a;Gustafson, et al, 2022). About the inheritance manner of ADAMTSL4-related eye disorders, previous studies exhibit major in recessive manner (Ahram et al, 2009;Aragon-Martin et al, 2010;Dollfus et al, 2010;Christensen et al, 2010;Chandra et al, 2012;Reinstein et al, 2016;van Bysterveldt et al, 2017;Gustafson, et al, 2022), and other manners including pseudodominant and dominant styles (Sharifi, et al, 2013;Scanga and Nischal, 2022;Chen TH, et al, 2022). Therefore, exploring the genotype-phenotype correlation will be extremely important for a better diagnosis, management, treatment and prognosis (Reich, et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Correlation between novel compound heterozygous ADAMTSL4 variants and primary phenotypes of ectopia lentis et pupillae

Zhao

Zhou

Zhang

et al. 2022

Experimental Eye Research

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“…Ectopia lentis is also caused by variants in FBN1, ADAMTS10, ADAMTS17 and LTBP2 , suggesting a functional relationship [ 48 ] in the regulation of zonule assembly. ADAMTSL4 variants phenocopy TGFβ receptor mutations in craniosynostosis [ 49 ], supporting a role in TGFβ regulation. During experimental heart failure in mice, cardiac ADAMTSL4 levels increase [ 9 ], indicating a role in the failing heart.…”

Section: Cardiovascular Disease Is a Major Cause Of Morbidity And Mor...mentioning

confidence: 99%

Emerging roles for the ADAMTS-like family of matricellular proteins in cardiovascular disease through regulation of the extracellular microenvironment

Rypdal,

Apte,

Lunde

2024

Mol Biol Rep

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Dysregulation of the extracellular matrix (ECM) occurs widely across cardiovascular pathologies. Recent work has revealed important roles for the «a disintegrin-like and metalloprotease domain with thrombospondin-type 1 motifs like” (ADAMTSL) family of secreted glycoproteins in cardiovascular tissues during development and disease. Key insights in this regard have come from naturally occurring gene mutations in humans and animals that result in severe diseases with cardiovascular manifestations or aortopathies. Expression of ADAMTSL genes is greatly increased in the myocardium during heart failure. Genetically modified mice recapitulate phenotypes of patients with ADAMTSL mutations and demonstrate important functions in the ECM. The novel functions thus disclosed are intriguing because, while these proteins are neither structural, nor proteases like the related ADAMTS proteases, they appear to act as regulatory, i.e., matricellular proteins. Evidence from genetic variants, genetically engineered mouse mutants, and in vitro investigations have revealed regulatory functions of ADAMTSLs related to fibrillin microfibrils and growth factor signaling. Interestingly, the ability to regulate transforming growth factor (TGF)β signaling may be a shared characteristic of some ADAMTSLs. TGFβ signaling is important in cardiovascular development, health and disease and a central driver of ECM remodeling and cardiac fibrosis. New strategies to target dysregulated TGFβ signaling are warranted in aortopathies and cardiac fibrosis. With their emerging roles in cardiovascular tissues, the ADAMTSL proteins may provide causative genes, diagnostic biomarkers and novel treatment targets in cardiovascular disease. Here, we discuss the relevance of ADAMTSLs to cardiovascular medicine.

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Mechanism of Disease: Recessive ADAMTSL4 Mutations and Craniosynostosis with Ectopia Lentis

Cited by 5 publications

References 51 publications

The value of genome-wide analysis in craniosynostosis

The value of genome-wide analysis in craniosynostosis

Correlation between novel compound heterozygous ADAMTSL4 variants and primary phenotypes of ectopia lentis et pupillae

Emerging roles for the ADAMTS-like family of matricellular proteins in cardiovascular disease through regulation of the extracellular microenvironment

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