<scp><i>ADAMTSL2</i></scp> gene variant in patients with features of autosomal dominant connective tissue disorders

Steinle, Jacob; Hossain, Waheeda A.; Lovell, Scott; Veatch, Olivia J.; Butler, Merlin G.

doi:10.1002/ajmg.a.62030

Cited by 10 publications

(7 citation statements)

References 32 publications

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“…Here, we showed that stb / stb mice exhibited dwarfism with shortened longitudinal bones and thickened skin, which are consistent with the abnormalities caused by mutated ADSMTSL2 / Adamtsl2 genes in humans (Le Goff et al 2008 ; Piccolo et al 2019 ; Allali et al 2011 ; Steinle et al 2021 ), dogs (Bader et al 2010 ) and mice (Hubmacher et al 2015 ). In addition, the present histological analysis of the tibial growth plate revealed that stb / stb mice showed a remarkable reduction in the hypertrophic chondrocyte layer.…”

Section: Discussionsupporting

confidence: 79%

A nonsense mutation in mouse Adamtsl2 causes uterine hypoplasia and an irregular estrous cycle

Iwanaga,

Tsuji,

Nishimura

et al. 2023

Mamm Genome

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The spontaneous mutation stubby (stb) in mice causes chondrodysplasia and male infertility due to impotence through autosomal recessive inheritance. In this study, we conducted linkage analysis to localize the stb locus within a 1.6 Mb region on mouse chromosome 2 and identified a nonsense mutation in Adamtsl2 of stb/stb mice. Histological analysis revealed disturbed endochondral ossification with a reduced hypertrophic chondrocyte layer and stiff skin with a thickened dermal layer. These phenotypes are similar to those observed in humans and mice with ADAMTSL2/Adamtsl2 mutations. Moreover, stb/stb female mice exhibited severe uterine hypoplasia at 5 weeks of age and irregular estrous cycles at 10 weeks of age. In normal mice, Adamtsl2 was more highly expressed in the ovary and pituitary gland than in the uterus, and this expression was decreased in stb/stb mice. These findings suggest that Adamtsl2 may function in these organs rather than in the uterus. Thus, we analyzed Gh expression in the pituitary gland and plasma estradiol and IGF1 levels, which are required for the development of the female reproductive tract. There was no significant difference in Gh expression and estradiol levels, whereas IGF1 levels in stb/stb mice were significantly reduced to 54–59% of those in +/+ mice. We conclude that Adamtsl2 is required for the development of the uterus and regulation of the estrous cycle in female mice, and decreased IGF1 may be related to these abnormalities.

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Section: Discussionsupporting

confidence: 79%

A nonsense mutation in mouse Adamtsl2 causes uterine hypoplasia and an irregular estrous cycle

Iwanaga,

Tsuji,

Nishimura

et al. 2023

Mamm Genome

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“…Fibrillin 1 is encoded by FBN1 , in which pathogenic variants underlie Marfan syndrome and ectopia lentis and have been reported for sporadic cases of SCAD . Paralogues of ADAMTSL4 , ADAMTSL6 ( alias of THSD4) , and ADAMTSL2 have been described in either aortic aneurysm, or probands with features of autosomal dominant connective tissue disorders, with similar functional roles to bind with fibrillin 1 and promote microfibril assembly . Combining evidence from unbiased GWAS, proband phenotypic correlation, functional roles in extracellular matrix microfibril formation, localization to the arterial tunica media vascular smooth muscle cells, support the consideration of ADAMTSL4 as a candidate gene for SCAD.…”

Section: Discussionmentioning

confidence: 99%

Burden of Rare Genetic Variants in Spontaneous Coronary Artery Dissection With High-risk Features

et al. 2022

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ImportanceThe emerging genetic basis of spontaneous coronary artery dissection (SCAD) has been defined as both partially complex and monogenic in some patients, involving variants predominantly in genes known to underlie vascular connective tissue diseases (CTDs). The effect of these genetic influences has not been defined in high-risk SCAD phenotypes, and the identification of a high-risk subgroup of individuals may help to guide clinical genetic evaluations of SCAD.ObjectiveTo identify and quantify the burden of rare genetic variation in individuals with SCAD with high-risk clinical features.Design, Setting, and ParticipantsWhole-exome sequencing (WES) was performed for subsequent case-control association analyses and individual variant annotation among individuals with high-risk SCAD. Genetic variants were annotated for pathogenicity by in-silico analysis of genes previously defined by sequencing for vascular CTDs and/or SCAD, as well as genes prioritized by genome-wide association study (GWAS) and colocalization of arterial expression quantitative trait loci. Unbiased genome-wide association analysis of the WES data was performed by comparing aggregated variants in individuals with SCAD to healthy matched controls or the Genome Aggregation Database (gnomAD). This study was conducted at a tertiary care center. Individuals in the Canadian SCAD Registry genetics study with a high-risk SCAD phenotype were selected and defined as peripartum SCAD, recurrent SCAD, or SCAD in an individual with family history of arteriopathy.Main Outcomes and MeasuresBurden of genetic variants defined by DNA sequencing in individuals with high-risk SCAD.ResultsThis study included a total of 336 participants (mean [SD] age, 53.0 [9.5] years; 301 female participants [90%]). Variants in vascular CTD genes were identified in 17.0% of individuals (16 of 94) with high-risk SCAD and were enriched (OR, 2.6; 95% CI, 1.6-4.2; P = 7.8 × 10−4) as compared with gnomAD, with leading significant signals in COL3A1 (OR, 13.4; 95% CI, 4.9-36.2; P = 2.8 × 10−4) and Loeys-Dietz syndrome genes (OR, 7.9; 95% CI, 2.9-21.2; P = 2.0 × 10−3). Variants in GWAS-prioritized genes, observed in 6.4% of individuals (6 of 94) with high-risk SCAD, were also enriched (OR, 3.6; 95% CI, 1.6-8.2; P = 7.4 × 10−3). Variants annotated as likely pathogenic or pathogenic occurred in 4 individuals, in the COL3A1, TGFBR2, and ADAMTSL4 genes. Genome-wide aggregated variant testing identified novel associations with peripartum SCAD.Conclusions and RelevanceIn this genetic study, approximately 1 in 5 individuals with a high-risk SCAD phenotype harbored a rare genetic variant in genes currently implicated for SCAD. Genetic screening in this subgroup of individuals presenting with SCAD may be considered.

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“…( 3 ) Furthermore, Steinle and colleagues described five unrelated individuals with dermatosparaxic Ehlers‐Danlos syndrome (dEDS) presenting with generalized joint hypermobility and fragility of the connective tissue caused by an autosomal dominant variant in ADAMTSL2 (c.1261G>A, p.(Gly421Ser)). ( 25 ) The contrasting clinical features of connective tissue laxity in dEDS versus tissue rigidity in GPHYSD1 and Al‐Gazali skeletal dysplasias suggests the possible gain‐of‐function effect of the p.(Gly421Ser) variant and thus further expands the spectrum of ADAMTSL2‐related disorders.…”

Section: Discussionmentioning

confidence: 99%

Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders

Batkovskyte

McKenzie

Taylan

et al. 2020

Journal of Bone and Mineral Research

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Lethal short‐limb skeletal dysplasia Al‐Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al‐Gazali type, is an ultra‐rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al‐Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short‐limb skeletal dysplasia Al‐Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease‐causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al‐Gazali skeletal dysplasia and identifies it as a semi‐lethal part of the spectrum of ADAMTSL2‐related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease‐causing variants might be located. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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ADAMTSL2 gene variant in patients with features of autosomal dominant connective tissue disorders

Cited by 10 publications

References 32 publications

A nonsense mutation in mouse Adamtsl2 causes uterine hypoplasia and an irregular estrous cycle

A nonsense mutation in mouse Adamtsl2 causes uterine hypoplasia and an irregular estrous cycle

Burden of Rare Genetic Variants in Spontaneous Coronary Artery Dissection With High-risk Features

Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders

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