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TASP1 mutation in a female with craniofacial anomalies, anterior segment dysgenesis, congenital immunodeficiency and macrocytic anemia.

ABSTRACT: BACKGROUND:Threonine Aspartase 1 (Taspase 1) is a highly conserved site-specific protease whose substrates are broad-acting nuclear transcription factors that govern diverse biological programs, such as organogenesis, oncogenesis, and tumor progression. To date, no single base pair mutations in Taspase 1 have been implicated in human disease. METHODS:A female infant with a new pattern of diagnostic abnormalities was identified, including severe craniofacial anomalies, anterior and posterior segment dysgenesis, immunodeficiency, and macrocytic anemia. Trio-based whole exome sequencing was performed to identify disease-causing variants. RESULTS:Whole exome sequencing revealed a normal female karyotype (46,XX) without increased regions of homozygosity. The proband was heterozygous for a de novo missense variant, c.1027G>A predicting p.(Val343Met), in the TASP1 gene (NM_017714.2). This variant has not been observed in population databases and is predicted to be deleterious. CONCLUSION:One human patient has been reported previously with a large TASP1 deletion and substantial evidence exists regarding the role of several known Taspase 1 substrates in human craniofacial and hematopoietic disorders. Moreover, Taspase 1 deficiency in mice results in craniofacial, ophthalmological and structural brain defects. Taken together, there exists substantial evidence to conclude that the TASP1 variant, p.(Val343Met), is pathogenic in this patient.

SUBMITTER: Balkin DM

PROVIDER: S-EPMC6732342 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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TASP1 mutation in a female with craniofacial anomalies, anterior segment dysgenesis, congenital immunodeficiency and macrocytic anemia.

Balkin Daniel M DM Poranki Menitha M Forester Craig M CM Dorsey Morna J MJ Slavotinek Anne A Pomerantz Jason H JH

Molecular genetics & genomic medicine 20190727 9

<h4>Background</h4>Threonine Aspartase 1 (Taspase 1) is a highly conserved site-specific protease whose substrates are broad-acting nuclear transcription factors that govern diverse biological programs, such as organogenesis, oncogenesis, and tumor progression. To date, no single base pair mutations in Taspase 1 have been implicated in human disease.<h4>Methods</h4>A female infant with a new pattern of diagnostic abnormalities was identified, including severe craniofacial anomalies, anterior and ...[more]

PMID: 31350873

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Project description:BackgroundCongenital cataracts are clinically and genetically heterogeneous with more than 45 known loci and 38 identified genes. They can occur as isolated defects or in association with anterior segment developmental anomalies. One of the disease genes for congenital cataract with or without anterior segment dysgenesis (ASD) is PITX3, encoding a transcription factor with a crucial role in lens and anterior segment development. Only five unique PITX3 mutations have been described, of which the 17-bp duplication c.640_656dup, p.(Gly220Profs*95), is the most common one and the only one known to cause cataract with ASD. The aim of this study was to perform a genetic study of the PITX3 gene in five probands with autosomal dominant congenital cataract (ADCC) and ASD, to compare their clinical presentations to previously reported PITX3-associated phenotypes and to functionally evaluate the PITX3 mutations found.MethodsSanger sequencing of the coding region and targeted exons of PITX3 was performed in probands and family members respectively. Transactivation, DNA-binding and subcellular localization assays were performed for the PITX3 mutations found. Ophthalmological examinations included visual acuity measurement, slit-lamp biomicroscopy, tonometry and fundoscopy.ResultsIn four Belgian families with ADCC and ASD the recurrent 17-bp duplication c.640_656dup, p.(Gly220Profs*95), was found in a heterozygous state. A novel PITX3 mutation c.573del, p.(Ser192Alafs*117), was identified in heterozygous state in a Belgo-Romanian family with a similar phenotype. Functional assays showed that this novel mutation retains its nuclear localization but results in decreased DNA-binding and transactivation activity, similar to the recurrent duplication.ConclusionsOur study identified a second PITX3 mutation leading to congenital cataract with ASD. The similarity in phenotypic expression was substantiated by our in vitro functional studies which demonstrated comparable molecular consequences for the novel p.(Ser192Alafs*117) and the recurrent p.(Gly220Profs*95) mutations.

Dataset Information

TASP1 mutation in a female with craniofacial anomalies, anterior segment dysgenesis, congenital immunodeficiency and macrocytic anemia.

Publications

TASP1 mutation in a female with craniofacial anomalies, anterior segment dysgenesis, congenital immunodeficiency and macrocytic anemia.

Similar Datasets

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