Mutations in mammalian tolloid-like 1 gene detected in adult patients with ASD

Stańczak, Paweł; Witecka, Joanna; Szydło, Anna; Gutmajster, Ewa; Lisik, Małgorzata; Auguściak‐Duma, Aleksandra; Tarnowski, Maciej; Czekaj, Tomasz M; Czekaj, Hanna; Sieroń, Aleksander

doi:10.1038/ejhg.2008.175

Cited by 29 publications

(22 citation statements)

References 39 publications

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“…After 10 dpc, mTLL1 is more broadly expressed, but mTLL1-null mice die at ϳ13.5 dpc from deficits apparently confined to the cardiovascular system (30). In humans, non-synonymous polymorphisms have been reported in mTLL1 coding sequences in several patients with atrial septal defects (36), although the significance of these findings remains to be determined.…”

Section: B/tp Distributions and General Functionsmentioning

confidence: 95%

Metalloproteinases in Drosophila to Humans That Are Central Players in Developmental Processes

Muir

Greenspan

2011

Journal of Biological Chemistry

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Many secreted proteins are synthesized as precursors with propeptides that must be cleaved to yield the mature functional form of the molecule. In addition, various growth factors occur in extracellular latent complexes with protein antagonists and are activated upon cleavage of such antagonists. Research in the separate fields of embryonic patterning and extracellular matrix formation has identified members of the BMP1/Tolloid-like family of metalloproteinases as key players in these types of biosynthetic processing events in species ranging from Drosophila to humans. Bone morphogenic proteins (BMPs)2 were first defined by the ability to induce de novo bone formation and were first identified in bone extracts (1). Although all other BMPs are members of the TGF␤ superfamily of growth factors, BMP1 is a metalloproteinase, the first demonstrated role of which was as a procollagen C-proteinase (pCP) (2) that cleaves C-propeptides from procollagen precursors to produce mature monomers of the major fibrillar collagens I-III. This activity is crucial to bone biology, as collagen I is the major protein component of bone and is essential to bone structure/function. After initial cloning of mammalian BMP1, Tolloid (TLD), the protein product of a zygotically active gene involved in dorsoventral patterning of Drosophila embryos, was shown to have a domain structure resembling that of BMP1 (3) and was later shown to exert patterning effects by activating the TGF␤-like BMP decapentaplegic (DPP) (4). Subsequently, BMP1 and TLD have become prototypes of the BMP1/TLD-like proteinase (B/TP) family. B/TPs in a broad range of species are now implicated in processes that include extracellular matrix (ECM) formation and mineralization, embryonic patterning, growth factor activation, and generation of anti-angiogenic protein fragments, all via cleavage of a growing list of substrates.

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Section: B/tp Distributions and General Functionsmentioning

confidence: 95%

Metalloproteinases in Drosophila to Humans That Are Central Players in Developmental Processes

Muir

Greenspan

2011

Journal of Biological Chemistry

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“…However, this child also had a de novo 17q deletion that was considered pathogenic. The deleted region on 4q32 harbors the TLL1 gene, in which heterozygous mutations have been associated with atrial septal defects, 22 and large deletions of 4q have also been reported in association with congenital heart defects. 23 Because the father was already aware of this deletion, the variant was reported.…”

Section: Variants Of Uncertain Significancementioning

confidence: 99%

A prospective study of the clinical utility of prenatal chromosomal microarray analysis in fetuses with ultrasound abnormalities and an exploration of a framework for reporting unclassified variants and risk factors

Brady

Chiaie

Christenhusz

et al. 2014

Genetics in Medicine

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Original research article INTRODUCTIONConventional karyotyping has been considered the gold standard for routine prenatal genetic diagnosis for many decades now, allowing for microscopic visualization and inspection of chromosomes and thus detection of numerical and structural chromosomal rearrangements. The main limitations are the resolution achieved by G-banding, which is limited to 5-10 Mb at best, and the requirement for cultured cells, needing a minimum of 8-10 days. The introduction of targeted methods of analysis such as fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) overcome the time constraints and resolution limitations inherent to karyotyping but do not provide a genome-wide analysis.1 More recently, molecular karyotyping using genomic microarrays has reached mainstream use in the postnatal diagnostic setting, providing a genome-wide screen for genomic imbalances at a far superior resolution to karyotyping.2 A number of studies have demonstrated the feasibility of prenatal diagnosis by genomic arrays using a variety of platforms, 3-7 but challenges remain in applying high-resolution genomic arrays to prenatal diagnosis. 6,8,9 One of the major ethical issues often raised is how to deal with variants of uncertain significance (VOUS) or risk loci, the detection of which leads to additional challenges for genetic counseling of parents. Furthermore, array analysis may reveal an imbalance for known "risk loci" where the future penetrance is uncertain or may be associated with variable expression. The penetrance risks for a number of recurrent copy-number variations (CNVs) have been estimated based on the frequencies in patients and controls. [10][11][12] However, although it is possible to calculate a populationbased risk, it is impossible in the prenatal setting to predict the phenotypic outcome in the child. Purpose:To evaluate the clinical utility of chromosomal microarrays for prenatal diagnosis by a prospective study of fetuses with abnormalities detected on ultrasound. Methods: Patients referred for prenatal diagnosis due to ultrasound anomalies underwent analysis by array comparative genomic hybridization as the first-tier diagnostic test.Results: A total of 383 prenatal samples underwent analysis by array comparative genomic hybridization. Array analysis revealed causal imbalances in a total of 9.6% of patients (n = 37). Submicroscopic copy-number variations were detected in 2.6% of patients (n = 10/37), and arrays added valuable information over conventional karyotyping in 3.9% of patients (n = 15/37). We highlight a novel advantage of arrays; a 500-kb paternal insertional translocation is the likely driver of a de novo unbalanced translocation, thus improving recurrence risk calculation in this family. Variants of uncertain significance were revealed in 1.6% of patients (n = 6/383). Conclusion:We demonstrate the added value of chromosomal microarrays for prenatal diagnosis in the presence of ultrasound anomalies. We advocate reporting back on...

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“…TLL1 encodes the astacin-like, zinc-dependent, metalloprotease Tolloid-like protein 1, a gene in which mutations have previously been identified in sporadic cases of ASD. 24 An A to G transition at nucleotide position 787 that predicted an amino acid change from an isoleucine to a valine at residue 263 (TLL1 Ile263Val, NM_001204760) was identified in an affected member (II-1) and not in an unaffected member, II-6 (Figure 2A–D). This mutation causes an amino acid change that occurs at a highly conserved residue in the metalloprotease active domain, which is required for TLL1’s protease activity (Figure 2E and 2F, Supplemental Table 3).…”

Section: Resultsmentioning

confidence: 99%

“…41 TLL1 has not been that well studied in human CHD, but heterozygous mutations have been reported in patients with ASD. 24 The Ile263Val (I263V) variant identified in TLL1 is considered likely pathogenic based on several lines of evidence. It was identified in the only available affected individual and not in one unaffected individual in family D. It is very rare in the general population, identified in only 1 out of 60,650 individuals in the ExAC database, and is predicted to be pathogenic by bioinformatic analysis.…”

Section: Discussionmentioning

confidence: 99%

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Utilization of Whole Exome Sequencing to Identify Causative Mutations in Familial Congenital Heart Disease

LaHaye

Corsmeier

Basu

et al. 2016

Circ Cardiovasc Genet

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Background Congenital heart disease (CHD) is the most common type of birth defect with family and population based studies supporting a strong genetic etiology for CHD. The goal of this study was to determine if a whole exome sequencing (WES) approach could identify pathogenic segregating variants in multiplex CHD families. Methods and Results WES was performed on 9 kindreds with familial CHD, 4 with atrial septal defects (ASD), 2 with patent ductus arteriosus (PDA), 2 with tetralogy of Fallot (TOF) and 1 with pulmonary valve dysplasia. Rare variants (<1% minor allele frequency) that segregated with disease were identified by WES, and variants in 69 CHD candidate genes were further analyzed. These selected variants were subjected to in silico analysis to predict pathogenicity and resulted in the discovery of likely pathogenic mutations in 3/9 (33%) families. A GATA4 mutation in the transactivation domain, p.G115W, was identified in familial ASD and demonstrated decreased transactivation ability in vitro. A p.I263V mutation in TLL1 was identified in an ASD kindred and is predicted to affect the enzymatic functionality of TLL1. A disease segregating splice donor site mutation in MYH11 (c.4599+1delG) was identified in familial PDA and found to disrupt normal splicing of Myh11 mRNA in the affected individual. Conclusions Our findings demonstrate the clinical utility of WES to identify causative mutations in familial CHD and demonstrate the successful use of a CHD candidate gene list to allow for a more streamlined approach enabling rapid prioritization and identification of likely pathogenic variants from large WES data sets. Clinical Trial Registration https://clinicaltrials.gov; Unique Identifier: NCT0112048.

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Mutations in mammalian tolloid-like 1 gene detected in adult patients with ASD

Cited by 29 publications

References 39 publications

Metalloproteinases in Drosophila to Humans That Are Central Players in Developmental Processes

Metalloproteinases in Drosophila to Humans That Are Central Players in Developmental Processes

A prospective study of the clinical utility of prenatal chromosomal microarray analysis in fetuses with ultrasound abnormalities and an exploration of a framework for reporting unclassified variants and risk factors

Utilization of Whole Exome Sequencing to Identify Causative Mutations in Familial Congenital Heart Disease

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