Skip to main content

Advertisement

SpringerLink
Log in

Identification and In Silico Characterization of a Novel Point Mutation within the Phosphatidylinositol Glycan Anchor Biosynthesis Class G Gene in an Iranian Family with Intellectual Disability

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Intellectual disability (ID) is characterized by limited mental ability and adaptive behavior that imposes a heavy burden on the patients’ families and the health care system. This study was aimed at determining the molecular aspect of nonsyndromic ID, in a family from South Khorasan Province in Iran. Exome sequencing was performed, as well as complete clinical examinations of the family. Afterward, in silico studies have been done to examine the changes that occurred in the protein structure, in association with the ID phenotype. The PIGG (NC_000004.12) mutation was found on Chr 4:517639G>A, and this chromosomal location was proposed as the disorder-causing variant. This Arg658Gln alteration was confirmed by Sanger sequencing, using specific primers for PIGG. In conclusion, our study indicated a novel mutation in the PIGG in the affected family. This mutation is a novel variant (p. R658Q) with an autosomal recessive inheritance pattern. These findings could improve genetic counseling in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  • Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249

    Article  CAS  Google Scholar 

  • Almeida AM, Murakami Y, Layton DM, Hillmen P, Sellick GS, Maeda Y, Richards S, Patterson S, Kotsianidis I, Mollica L, Crawford DH, Baker A, Ferguson M, Roberts I, Houlston R, Kinoshita T, Karadimitris A (2006) Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency. Nat Med 12:846–851

    Article  CAS  Google Scholar 

  • Almeida AM, Murakami Y, Baker A, Maeda Y, Roberts IAG, Kinoshita T, Layton DM, Karadimitris A (2007) Targeted therapy for inherited GPI deficiency. N Engl J Med 356:1641–1647

    Article  CAS  Google Scholar 

  • Capriotti E, Altman RB, Bromberg Y (2013) Collective judgment predicts disease-associated single nucleotide variants. BMC Genomics 14:S2

    Article  Google Scholar 

  • De Ligt J et al (2012) Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 367:1921–1929

    Article  Google Scholar 

  • Hamdan FF et al (2009) Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation N Engl J med 360:599-605

  • Hamdan et al (2014) De novo mutations in moderate or severe intellectual disability. PLOS e1004772 https://www.ncbi.nlm.nih.gov/gene/54872

  • Inlow JK, Restifo LL (2004) Molecular and comparative genetics of mental retardation. Genetics 166:835–881

    Article  CAS  Google Scholar 

  • Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee YH, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB, Mardis ER, Wilson RK, Schatz MC, McCombie WR, Wigler M (2012) De novo gene disruptions in children on the autistic spectrum. Neuron 74:285–299

    Article  CAS  Google Scholar 

  • Johnston JJ, Gropman AL, Sapp JC, Teer JK, Martin JM, Liu CF, Yuan X, Ye Z, Cheng L, Brodsky RA, Biesecker LG (2012) The phenotype of a germline mutation in PIGA: the gene somatically mutated in paroxysmal nocturnal hemoglobinuria. Am J Hum Genet 90:295–300

    Article  CAS  Google Scholar 

  • Kinoshita T (2014) Biosynthesis and deficiencies of glycosylphosphatidylinositol. Proc Jpn Acad Ser Biol Sci 90:130–143

    Article  CAS  Google Scholar 

  • Kochinke K, Zweier C, Nijhof B, Fenckova M, Cizek P, Honti F, Keerthikumar S, Oortveld MAW, Kleefstra T, Kramer JM, Webber C, Huynen MA, Schenck A (2016) Systematic phenomics analysis deconvolutes genes mutated in intellectual disability into biologically coherent modules. Am J Hum Genet 98:149–164

    Article  CAS  Google Scholar 

  • Kortum F, Das S, Flindt M, Morris-Rosendahl DJ, Stefanova I, Goldstein A, Horn D, Klopocki E, Kluger G, Martin P, Rauch A, Roumer A, Saitta S, Walsh LE, Wieczorek D, Uyanik G, Kutsche K, Dobyns WB (2011) The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. J Med Genet 48:396–406

    Article  Google Scholar 

  • Krawitz PM, Murakami Y, Hecht J, Krüger U, Holder SE, Mortier GR, Delle Chiaie B, de Baere E, Thompson MD, Roscioli T, Kielbasa S, Kinoshita T, Mundlos S, Robinson PN, Horn D (2012) Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation. Am J Hum Genet 91:146–151

    Article  CAS  Google Scholar 

  • Leonard H, Wen X (2002) The epidemiology of mental retardation: challenges and opportunities in the new millennium. Men Retard Dev Disabil Res Rev 8:117–134

    Article  Google Scholar 

  • Makrythanasis P, Kato M, Zaki MS, Saitsu H, Nakamura K, Santoni FA, Miyatake S, Nakashima M, Issa MY, Guipponi M, Letourneau A, Logan CV, Roberts N, Parry DA, Johnson CA, Matsumoto N, Hamamy H, Sheridan E, Kinoshita T, Antonarakis SE, Murakami Y (2016) Pathogenic variants in PIGG cause intellectual disability with seizures and hypotonia. Am J Hum Genet 98:615–626

    Article  CAS  Google Scholar 

  • Maydan G, Noyman I, Har-Zahav A, Neriah ZB, Pasmanik-Chor M, Yeheskel A, Albin-Kaplanski A, Maya I, Magal N, Birk E, Simon AJ, Halevy A, Rechavi G, Shohat M, Straussberg R, Basel-Vanagaite L (2011) Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN. J Med Genet 48:383–389

    Article  CAS  Google Scholar 

  • Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH (2010) Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 86:749–764

    Article  CAS  Google Scholar 

  • Moeschler JB, Shevell M (2014) Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics 134:e903–e918

    Article  Google Scholar 

  • National Academies of Sciences E, and Medicine, Instituteof Medicine, Board on Children, Youth, and Families, Board on theHealth of Select Populations, Committee to Evaluate the Supplemental Security Income Disability Program for Children with Mental Disorders (2015) Prevalence of intellectual disabilities. In: Wu JT, Boat TF (eds) Mental disorders and disabilities among low-income children. National Academies Press, Washington

    Google Scholar 

  • Novo-Filho GM, Montenegro MM, Zanardo ÉA, Dutra RL, Dias AT, Piazzon FB, Costa TVMM, Nascimento AM, Honjo RS, Kim CA, Kulikowski LD (2016) Subtelomeric copy number variations: the importance of 4p/4q deletions in patients with congenital anomalies and developmental disability. Cytogenet Genome Res 149:241–246

    Article  CAS  Google Scholar 

  • Nykamp K et al (2017) Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med 19:1105–1117

    Article  Google Scholar 

  • Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, Albrecht B, Bartholdi D, Beygo J, di Donato N, Dufke A, Cremer K, Hempel M, Horn D, Hoyer J, Joset P, Röpke A, Moog U, Riess A, Thiel CT, Tzschach A, Wiesener A, Wohlleber E, Zweier C, Ekici AB, Zink AM, Rump A, Meisinger C, Grallert H, Sticht H, Schenck A, Engels H, Rappold G, Schröck E, Wieacker P, Riess O, Meitinger T, Reis A, Strom TM (2012) Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380:1674–1682

    Article  CAS  Google Scholar 

  • Raymond FL (2006) X linked mental retardation: a clinical guide. J Med Genet 43:193–200

    Article  CAS  Google Scholar 

  • Stevenson RE, Procopio-Allen AM, Schroer RJ, Collins JS (2003) Genetic syndromes among individuals with mental retardation. Am J Med Genetics A 123:29–32

    Article  Google Scholar 

  • Topper S, Ober C, Das S (2011) Exome sequencing and the genetics of intellectual disability. Clin Genet 80:117–126

    Article  CAS  Google Scholar 

  • Zhao JJ, Halvardson J, Knaus A, Georgii-Hemming P, Baeck P, Krawitz PM, Thuresson AC, Feuk L (2017) Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function. Hum Mutat 38:1394–1401

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank all the subjects who willingly participated in this research.

Funding

This work was financially supported by a research grant from Birjand University of Medical Science.

Author information

Authors and Affiliations

  1. Student Research Committee & Department of Molecular Medicine, Birjand University of Medical Sciences, Birjand, Iran

    Negin Parsamanesh

  2. Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran

    Hossein Safarpour

  3. Nikou Counseling Center, Social Welfare Organization of South Khorasan Province, Birjand, Iran

    Shokoofe Etesam

  4. Social Welfare Organization of South Khorasan Province, Birjand, Iran

    Aazam Ahmadi Shadmehri

  5. Cardiovascular Diseases Research Center & Department of Molecular Medicine, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran

    Ebrahim Miri-Moghaddam

Authors
  1. Negin Parsamanesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hossein Safarpour
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shokoofe Etesam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aazam Ahmadi Shadmehri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ebrahim Miri-Moghaddam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Aazam Ahmadi Shadmehri or Ebrahim Miri-Moghaddam.

Ethics declarations

A clinical geneticist obtained all exams and informed consent from every member of the family. In this study, the entire procedures were conducted according to the Helsinki Declaration and ethical standards of the institutional research committee. The ethics code was taken from Birjand University of Medical Sciences (Ir.bums. REC.1396.350).

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Parsamanesh, N., Safarpour, H., Etesam, S. et al. Identification and In Silico Characterization of a Novel Point Mutation within the Phosphatidylinositol Glycan Anchor Biosynthesis Class G Gene in an Iranian Family with Intellectual Disability. J Mol Neurosci 69, 538–545 (2019). https://doi.org/10.1007/s12031-019-01376-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-019-01376-y

Keywords

Search

Navigation