Truncating biallelic variant in DNAJA1, encoding the co-chaperone Hsp40, is associated with intellectual disability and seizures

  • Saud Alsahli
  • Ahmed Alfares
  • Francisco J. Guzmán-Vega
  • Stefan T. Arold
  • Duaa Ba-Armah
  • Fuad Al MutairiEmail author
Short Communication


Intellectual disability poses a huge burden on the health care system, and it is one of the most common referral reasons to the genetic and child neurology clinic. Intellectual disability (ID) is genetically heterogeneous, and it is associated with several other neurological conditions. Exome sequencing is a robust genetic tool and has revolutionized the process of molecular diagnosis and novel gene discovery. Besides its diagnostic clinical value, novel gene discovery is prime in reverse genetics, when human mutations help to understand the function of a gene and may aid in better understanding of the human brain and nervous system. Using WES, we identified a biallelic truncating variant in DNAJA1 gene (c.511C>T p.(Gln171*) in a multiplex Saudi consanguineous family. The main phenotype shared between the siblings was intellectual disability and seizure disorder.


Intellectual disability Seizure disorder DNAJA1 Exome sequencing Chaperonopathy Chaperone Co-chaperone Hsp40 



We would thank the studied family for their enthusiastic participation.

Contributorship statement

SA and FA created the presented idea and wrote the manuscript. SA, DB, and FA contributed to the patient care and diagnosis. SA, AA, DB, and FA prepared the tables. SA, AA, STA, FJG, and FA prepared the figures. SA, AA, STA, FJG, DB, and FA edited the manuscript.

Funding information

The research by STA and FJGV reported in this publication was supported by funding from King Abdullah University of Science and Technology (KAUST) through the baseline fund and the Office of Sponsored Research (OSR), under award number FCC/1/1976-25-01.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10048_2019_573_MOESM1_ESM.docx (14 kb)
Table S1 Regions of homozygosity in the current cohort. (DOCX 14 kb)
10048_2019_573_MOESM2_ESM.docx (15 kb)
Table S2 Detailed clinical synopsis (DOCX 15 kb)


  1. 1.
    American Psychiatric Association., American Psychiatric Association. DSM-5 Task Force (2013) Diagnostic and statistical manual of mental disorders: DSM-5, 5th edn. American Psychiatric Association, Washington, D.CCrossRefGoogle Scholar
  2. 2.
    Anazi S, Maddirevula S, Faqeih E, Alsedairy H, Alzahrani F, Shamseldin HE, Patel N, Hashem M, Ibrahim N, Abdulwahab F, Ewida N, Alsaif HS, Al Sharif H, Alamoudi W, Kentab A, Bashiri FA, Alnaser M, AlWadei AH, Alfadhel M, Eyaid W, Hashem A, Al Asmari A, Saleh MM, AlSaman A, Alhasan KA, Alsughayir M, Al Shammari M, Mahmoud A, Al-Hassnan ZN, Al-Husain M, Osama Khalil R, Abd El Meguid N, Masri A, Ali R, Ben-Omran T, El Fishway P, Hashish A, Ercan Sencicek A, State M, Alazami AM, Salih MA, Altassan N, Arold ST, Abouelhoda M, Wakil SM, Monies D, Shaheen R, Alkuraya FS (2017) Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Mol Psychiatry 22(4):615–624. CrossRefGoogle Scholar
  3. 3.
    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(5):749–764. CrossRefGoogle Scholar
  4. 4.
    Stark Z, Schofield D, Martyn M, Rynehart L, Shrestha R, Alam K, Lunke S, Tan TY, Gaff CL, White SM (2019) Does genomic sequencing early in the diagnostic trajectory make a difference? A follow-up study of clinical outcomes and cost-effectiveness. Genet Med 21(1):173–180. CrossRefGoogle Scholar
  5. 5.
    Alfares A, Alfadhel M, Wani T, Alsahli S, Alluhaydan I, Al Mutairi F, Alothaim A, Albalwi M, Al Subaie L, Alturki S, Al-Twaijri W, Alrifai M, Al-Rumayya A, Alameer S, Faqeeh E, Alasmari A, Alsamman A, Tashkandia S, Alghamdi A, Alhashem A, Tabarki B, AlShahwan S, Hundallah K, Wali S, Al-Hebbi H, Babiker A, Mohamed S, Eyaid W, Zada AAP (2017) A multicenter clinical exome study in unselected cohorts from a consanguineous population of Saudi Arabia demonstrated a high diagnostic yield. Mol Genet Metab 121(2):91–95. CrossRefGoogle Scholar
  6. 6.
    Anazi S, Maddirevula S, Salpietro V, Asi YT, Alsahli S, Alhashem A, Shamseldin HE, AlZahrani F, Patel N, Ibrahim N, Abdulwahab FM, Hashem M, Alhashmi N, Al Murshedi F, Al Kindy A, Alshaer A, Rumayyan A, Al Tala S, Kurdi W, Alsaman A, Alasmari A, Banu S, Sultan T, Saleh MM, Alkuraya H, Salih MA, Aldhalaan H, Ben-Omran T, Al Musafri F, Ali R, Suleiman J, Tabarki B, El-Hattab AW, Bupp C, Alfadhel M, Al Tassan N, Monies D, Arold ST, Abouelhoda M, Lashley T, Houlden H, Faqeih E, Alkuraya FS (2017) Expanding the genetic heterogeneity of intellectual disability. Hum Genet 136(11–12):1419–1429. CrossRefGoogle Scholar
  7. 7.
    Harripaul R, Vasli N, Mikhailov A, Rafiq MA, Mittal K, Windpassinger C, Sheikh TI, Noor A, Mahmood H, Downey S, Johnson M, Vleuten K, Bell L, Ilyas M, Khan FS, Khan V, Moradi M, Ayaz M, Naeem F, Heidari A, Ahmed I, Ghadami S, Agha Z, Zeinali S, Qamar R, Mozhdehipanah H, John P, Mir A, Ansar M, French L, Ayub M, Vincent JB (2018) Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families. Mol Psychiatry 23(4):973–984. CrossRefGoogle Scholar
  8. 8.
    Musante L, Ropers HH (2014) Genetics of recessive cognitive disorders. Trends Genet 30(1):32–39. CrossRefGoogle Scholar
  9. 9.
    Ozand PT, Devol EB, Gascon GG (1992) Neurometabolic diseases at a national referral center: five years experience at the King Faisal Specialist Hospital and Research Centre. J Child Neurol 7(Suppl):S4–S11.
  10. 10.
    Alkuraya FS (2014) Genetics and genomic medicine in Saudi Arabia. Mol Genet Genomic Med 2(5):369–378. CrossRefGoogle Scholar
  11. 11.
    Fontaine SN, Zheng D, Sabbagh JJ, Martin MD, Chaput D, Darling A, Trotter JH, Stothert AR, Nordhues BA, Lussier A, Baker J, Shelton L, Kahn M, Blair LJ, Stevens SM Jr, Dickey CA (2016) DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative-associated proteins. EMBO J 35(14):1537–1549. CrossRefGoogle Scholar
  12. 12.
    Wiszniewska J, Bi W, Shaw C, Stankiewicz P, Kang SH, Pursley AN, Lalani S, Hixson P, Gambin T, Tsai CH, Bock HG, Descartes M, Probst FJ, Scaglia F, Beaudet AL, Lupski JR, Eng C, Cheung SW, Bacino C, Patel A (2014) Combined array CGH plus SNP genome analyses in a single assay for optimized clinical testing. Eur J Hum Genet 22(1):79–87. CrossRefGoogle Scholar
  13. 13.
    Alsahli S, Arold ST, Alfares A, Alhaddad B, Al Balwi M, Kamsteeg EJ, Al-Twaijri W, Alfadhel M (2018) KIF16B is a candidate gene for a novel autosomal-recessive intellectual disability syndrome. Am J Med Genet A 176(7):1602–1609. CrossRefGoogle Scholar
  14. 14.
    Yang J, Zhang Y (2015) I-TASSER server: new development for protein structure and function predictions. Nucleic Acids Res 43(W1):W174–W181. CrossRefGoogle Scholar
  15. 15.
    Kampinga HH, Hageman J, Vos MJ, Kubota H, Tanguay RM, Bruford EA, Cheetham ME, Chen B, Hightower LE (2009) Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 14(1):105–111. CrossRefGoogle Scholar
  16. 16.
    Harris JM, Nguyen PP, Patel MJ, Sporn ZA, Hines JK (2014) Functional diversification of hsp40: distinct j-protein functional requirements for two prions allow for chaperone-dependent prion selection. PLoS Genet 10(7):e1004510. CrossRefGoogle Scholar
  17. 17.
    Finka A, Mattoo RU, Goloubinoff P (2016) Experimental milestones in the discovery of molecular chaperones as polypeptide unfolding enzymes. Annu Rev Biochem 85:715–742. CrossRefGoogle Scholar
  18. 18.
    Keck M, Androsova G, Gualtieri F, Walker A, von Ruden EL, Russmann V, Deeg CA, Hauck SM, Krause R, Potschka H (2017) A systems level analysis of epileptogenesis-associated proteome alterations. Neurobiol Dis 105:164–178. CrossRefGoogle Scholar
  19. 19.
    Gorter JA, van Vliet EA, Aronica E, Breit T, Rauwerda H, Lopes da Silva FH, Wadman WJ (2006) Potential new antiepileptogenic targets indicated by microarray analysis in a rat model for temporal lobe epilepsy. J Neurosci 26(43):11083–11110. CrossRefGoogle Scholar
  20. 20.
    Hartl FU, Bracher A, Hayer-Hartl M (2011) Molecular chaperones in protein folding and proteostasis. Nature 475(7356):324–332. CrossRefGoogle Scholar
  21. 21.
    Suzuki T, Usuda N, Murata S, Nakazawa A, Ohtsuka K, Takagi H (1999) Presence of molecular chaperones, heat shock cognate (Hsc) 70 and heat shock proteins (Hsp) 40, in the postsynaptic structures of rat brain. Brain Res 816(1):99–110CrossRefGoogle Scholar
  22. 22.
    Gorenberg EL, Chandra SS (2017) The role of co-chaperones in synaptic proteostasis and neurodegenerative disease. Front Neurosci 11:248. CrossRefGoogle Scholar
  23. 23.
    Weiler IJ, Spangler CC, Klintsova AY, Grossman AW, Kim SH, Bertaina-Anglade V, Khaliq H, de Vries FE, Lambers FA, Hatia F, Base CK, Greenough WT (2004) Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses. Proc Natl Acad Sci U S A 101(50):17504–17509. CrossRefGoogle Scholar
  24. 24.
    Shigeoka T, Jung H, Jung J, Turner-Bridger B, Ohk J, Lin JQ, Amieux PS, Holt CE (2016) Dynamic axonal translation in developing and mature visual circuits. Cell 166(1):181–192. CrossRefGoogle Scholar
  25. 25.
    Younts TJ, Monday HR, Dudok B, Klein ME, Jordan BA, Katona I, Castillo PE (2016) Presynaptic protein synthesis is required for long-term plasticity of GABA release. Neuron 92(2):479–492. CrossRefGoogle Scholar
  26. 26.
    Burre J, Beckhaus T, Corvey C, Karas M, Zimmermann H, Volknandt W (2006) Synaptic vesicle proteins under conditions of rest and activation: analysis by 2-D difference gel electrophoresis. Electrophoresis 27(17):3488–3496. CrossRefGoogle Scholar
  27. 27.
    Elsayed LE, Drouet V, Usenko T, Mohammed IN, Hamed AA, Elseed MA, Salih MA, Koko ME, Mohamed AY, Siddig RA, Elbashir MI, Ibrahim ME, Durr A, Stevanin G, Lesage S, Ahmed AE, Brice A (2016) A novel nonsense mutation in DNAJC6 expands the phenotype of autosomal-recessive juvenile-onset Parkinson’s disease. Ann Neurol 79(2):335–337. CrossRefGoogle Scholar
  28. 28.
    Guarnieri FC, Pozzi D, Raimondi A, Fesce R, Valente MM, Delvecchio VS, Van Esch H, Matteoli M, Benfenati F, D’Adamo P, Valtorta F (2017) A novel SYN1 missense mutation in non-syndromic X-linked intellectual disability affects synaptic vesicle life cycle, clustering and mobility. Hum Mol Genet 26(23):4699–4714. CrossRefGoogle Scholar
  29. 29.
    Chia PH, Zhong FL, Niwa S, Bonnard C, Utami KH, Zeng R, Lee H, Eskin A, Nelson SF, Xie WH, Al-Tawalbeh S, El-Khateeb M, Shboul M, Pouladi MA, Al-Raqad M, Reversade B (2018) A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability. Elife 7.
  30. 30.
    Szabo A, Korszun R, Hartl FU, Flanagan J (1996) A zinc finger-like domain of the molecular chaperone DnaJ is involved in binding to denatured protein substrates. EMBO J 15(2):408–417CrossRefGoogle Scholar
  31. 31.
    Walker VE, Wong MJ, Atanasiu R, Hantouche C, Young JC, Shrier A (2010) Hsp40 chaperones promote degradation of the HERG potassium channel. J Biol Chem 285(5):3319–3329. CrossRefGoogle Scholar
  32. 32.
    Partemi S, Cestele S, Pezzella M, Campuzano O, Paravidino R, Pascali VL, Zara F, Tassinari CA, Striano S, Oliva A, Brugada R, Mantegazza M, Striano P (2013) Loss-of-function KCNH2 mutation in a family with long QT syndrome, epilepsy, and sudden death. Epilepsia 54(8):e112–e116. CrossRefGoogle Scholar
  33. 33.
    Zamorano-Leon JJ, Yanez R, Jaime G, Rodriguez-Sierra P, Calatrava-Ledrado L, Alvarez-Granada RR, Mateos-Caceres PJ, Macaya C, Lopez-Farre AJ (2012) KCNH2 gene mutation: a potential link between epilepsy and long QT-2 syndrome. J Neurogenet 26(3–4):382–386. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Saud Alsahli
    • 1
    • 2
  • Ahmed Alfares
    • 3
    • 4
  • Francisco J. Guzmán-Vega
    • 5
  • Stefan T. Arold
    • 5
  • Duaa Ba-Armah
    • 2
    • 6
  • Fuad Al Mutairi
    • 2
    • 7
    Email author
  1. 1.Department of Pediatric NeurologyTexas Children’s Hospital, Baylor College of MedicineHoustonUSA
  2. 2.King Abdullah International Medical Research Center (KAIMRC), College of MedicineKing Saud bin Abdulaziz University for Health SciencesRiyadhSaudi Arabia
  3. 3.Department of Pathology and Laboratory Medicine, King Abdulaziz Medical CityMinistry of National Guard-Health Affairs (MNGHA)RiyadhSaudi Arabia
  4. 4.Department of PediatricsQassim UniversityBuraydahSaudi Arabia
  5. 5.Division of Biological and Environmental Sciences and Engineering (BESE)King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC)ThuwalSaudi Arabia
  6. 6.Department of Pediatrics, King Abdulaziz Medical City, Division of Pediatric NeurologyMinistry of National Guard-Health Affairs (MNGHA)RiyadhSaudi Arabia
  7. 7.Division of Genetics, Department of Pediatrics, King Abdulaziz Medical CityMinistry of National Guard-Health Affairs (MNGHA)RiyadhSaudi Arabia

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