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      A novel compound heterozygous mutation of the SMARCAL1 gene leading to mild Schimke immune-osseous dysplasia: a case report

      case-report

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          Abstract

          Background

          Schimke immune-osseous dysplasia (SIOD, OMIM 242900) is characterized by spondyloepiphyseal dysplasia, T-cell deficiency, renal dysfunction and special facial features. SMARCAL1 gene mutations are determined in approximately 50% of patients diagnosed with SIOD.

          Case presentation

          The case presented here is that of a 6-year-old boy who was born at 33 weeks to healthy, non-consanguineous Chinese parents. He presented with short stature (95 cm; <3rd percentile) and proteinuria. Initially suspected of having IgM nephropathy, the patient was finally diagnosed with mild Schimke immune-osseous dysplasia. One novel mutation (p.R817H) and one well-known mutation (p.R645C) was identified in the SMARCAL1 gene.

          Conclusion

          This report describes a clinical and genetic diagnostic model of mild SIOD. It also highlights the importance of molecular testing or clinical diagnosis and the guidance it provides in disease prognosis.

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          Most cited references26

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          Two related superfamilies of putative helicases involved in replication, recombination, repair and expression of DNA and RNA genomes.

          A E Gorbalenya, E. V. Koonin, A P Donchenko … (1989)
          In the course of systematic analysis of protein sequences containing the purine NTP-binding motif, a new superfamily was delineated which included 25 established or putative helicases of Escherichia coli, yeast, insects, mammals, pox- and herpesviruses, a yeast mitochondrial plasmid and three groups of positive strand RNA viruses. These proteins contained 7 distinct highly conserved segments two of which corresponded to the "A" and "B" sites of the NTP-binding motif. Typical of the new superfamily was an abridged consensus for the "A" site, GxGKS/T, instead of the classical G/AxxxxGKS/T. Secondary structure predictions indicated that each of the conserved segments might constitute a separate structural unit centering at a beta-turn. All previously characterized mutations impairing the function of the yeast helicase RAD3 in DNA repair mapped to one of the conserved segments. A degree of similarity was revealed between the consensus pattern of conserved amino acid residues derived for the new superfamily and that of another recently described protein superfamily including a different set of prokaryotic, eukaryotic and viral (putative) helicases.
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            The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks.

            Rémy Bétous, Carol E. Bansbach, Jennifer C Lovejoy … (2009)
            Mutations in SMARCAL1 (HARP) cause Schimke immunoosseous dysplasia (SIOD). The mechanistic basis for this disease is unknown. Using functional genomic screens, we identified SMARCAL1 as a genome maintenance protein. Silencing and overexpression of SMARCAL1 leads to activation of the DNA damage response during S phase in the absence of any genotoxic agent. SMARCAL1 contains a Replication protein A (RPA)-binding motif similar to that found in the replication stress response protein TIPIN (Timeless-Interacting Protein), which is both necessary and sufficient to target SMARCAL1 to stalled replication forks. RPA binding is critical for the cellular function of SMARCAL1; however, it is not necessary for the annealing helicase activity of SMARCAL1 in vitro. An SIOD-associated SMARCAL1 mutant fails to prevent replication-associated DNA damage from accumulating in cells in which endogenous SMARCAL1 is silenced. Ataxia-telangiectasia mutated (ATM), ATM and Rad3-related (ATR), and DNA-dependent protein kinase (DNA-PK) phosphorylate SMARCAL1 in response to replication stress. Loss of SMARCAL1 activity causes increased RPA loading onto chromatin and persistent RPA phosphorylation after a transient exposure to replication stress. Furthermore, SMARCAL1-deficient cells are hypersensitive to replication stress agents. Thus, SMARCAL1 is a replication stress response protein, and the pleiotropic phenotypes of SIOD are at least partly due to defects in genome maintenance during DNA replication.
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              Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia.

              E. Jane Tizard, F Illies, Sander Rodrigo … (2002)
              Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.
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                Author and article information

                Contributors
                Shuaimei Liu: 719305071@qq.com
                Mingchao Zhang: zmchj99@163.com
                Mengxia Ni: nimengxia@126.com
                Peiran Zhu: 980346785@qq.com
                Xinyi Xia: +86 025 80863084 , xiaxynju@163.com
                Journal
                Journal ID (nlm-ta): BMC Pediatr
                Journal ID (iso-abbrev): BMC Pediatr
                Title: BMC Pediatrics
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1471-2431
                Publication date (Electronic): 28 December 2017
                Publication date PMC-release: 28 December 2017
                Publication date Collection: 2017
                Volume: 17
                Electronic Location Identifier: 217
                Affiliations
                [1 ]ISNI 0000 0001 0115 7868, GRID grid.440259.e, Department of Reproduction and Genetics, , Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, ; Nanjing, 210002 People’s Republic of China
                [2 ]ISNI 0000 0001 0115 7868, GRID grid.440259.e, National Clinical Research Center of Kidney Diseases, , Jinling Hospital, Nanjing University School of Medicine, ; Nanjing, 210016 People’s Republic of China
                Article
                Publisher ID: 968
                DOI: 10.1186/s12887-017-0968-8
                PMC ID: 5745888
                PubMed ID: 29282041
                SO-VID: 70dd0fe7-1ae6-4966-a332-26b62de7b8b2
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 20 July 2016
                Date accepted : 12 December 2017
                Funding
                Funded by: Key Foundation of Jiangsu Science and Technology Bureau
                Award ID: BM2015020
                Award Recipient :
                Funded by: Nanjing Science and Technology Development Project
                Award ID: 201503010
                Award Recipient :
                Funded by: Nanjing Science and Technology Project
                Award ID: 2014020008
                Funded by: foundation of Nanjing General Hospital of Nanjing Military Command, PLA
                Award ID: 2015046
                Award ID: 2014044
                Categories
                Subject: Case Report
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Pediatrics
                Keywords: schimke immune-osseous dysplasia,smarcal1,next generation sequencing,mutation analysis
                Data availability:
                ScienceOpen disciplines: Pediatrics
                Keywords: schimke immune-osseous dysplasia, smarcal1, next generation sequencing, mutation analysis

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