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Clinical characterization and further confirmation of the autosomal recessive SLC12A2 disease

Journal of Human Genetics volume 66, pages 689–695 (2021)Cite this article

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Abstract

Heterozygous pathogenic variants in SLC12A2 are reported in patients with nonsyndromic hearing loss. Recently, homozygous loss-of-function variants have been reported in two patients with syndromic intellectual disability, with or without hearing loss. However, the clinical and molecular spectrum of SLC12A2 disease has yet to be characterized and confirmed. Using whole-exome sequencing, we detected a homozygous splicing variant in four patients from two independent families with severe developmental delay, microcephaly, respiratory abnormalities, and subtle dysmorphic features, with or without congenital hearing loss. We also reviewed the reported cases with pathogenic variants associated with autosomal dominant and recessive forms of the SLC12A2 disease. About 50% of the cases have syndromic and nonsyndromic congenital hearing loss. All patients harboring the recessive forms of the disease presented with severe global developmental delay. Interestingly, all reported variants are located in the c-terminal domain, suggesting a critical role of this domain for the proper function of the encoded co-transporter protein. In conclusion, our study provides an additional confirmation of the autosomal recessive SLC12A2 disease.

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The data that support the findings of this study are available from the corresponding author upon request.

References

  1. Delpire E, Gagnon KB. Na(+) -K(+) -2Cl(-) Cotransporter (NKCC) physiological function in nonpolarized cells and transporting epithelia. Compr Physiol. 2018;8:871–901.

    Article  Google Scholar 

  2. Nin F, Yoshida T, Murakami S, Ogata G, Uetsuka S, Choi S. et al. Computer modeling defines the system driving a constant current crucial for homeostasis in the mammalian cochlea by integrating unique ion transports. NPJ Syst Biol Appl. 2017;3:24

    Article  Google Scholar 

  3. Wangemann P. Supporting sensory transduction: cochlear fluid homeostasis and the endocochlear potential. J Physiol. 2006;576:11–21.

    Article  CAS  Google Scholar 

  4. Dzhala VI, Talos DM, Sdrulla DA, Brumback AC, Mathews GC, Benke TA. et al. NKCC1 transporter facilitates seizures in the developing brain. Nat Med. 2005;11:1205–13.

    Article  CAS  Google Scholar 

  5. Sung KW, Kirby M, McDonald MP, Lovinger DM, Delpire E. Abnormal GABAA receptor-mediated currents in dorsal root ganglion neurons isolated from Na-K-2Cl cotransporter null mice. J Neurosci. 2000;20:7531–8.

    Article  CAS  Google Scholar 

  6. De Koninck Y. Altered chloride homeostasis in neurological disorders: a new target. Curr Opin Pharm. 2007;7:93–99.

    Article  Google Scholar 

  7. Hyde TM, Lipska BK, Ali T, Mathew SV, Law AJ, Metitiri OE. et al. Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia. J Neurosci. 2011;31:11088–95.

    Article  CAS  Google Scholar 

  8. Kahle KT, Staley KJ, Nahed BV, Gamba G, Hebert SC, Lifton RP. et al. Roles of the cation-chloride cotransporters in neurological disease. Nat Clin Pr Neurol. 2008;4:490–503.

    Article  CAS  Google Scholar 

  9. Kim JY, Liu CY, Zhang F, Duan X, Wen Z, Song J. et al. Interplay between DISC1 and GABA signaling regulates neurogenesis in mice and risk for schizophrenia. Cell. 2012;148:1051–64.

    Article  CAS  Google Scholar 

  10. Payne JA. Molecular operation of the cation chloride cotransporters: ion binding and inhibitor interaction. Curr Top Membr. 2012;70:215–37.

    Article  CAS  Google Scholar 

  11. Delpire E, Lu J, England R, Dull C, Thorne T. Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter. Nat Genet. 1999;22:192–5.

    Article  CAS  Google Scholar 

  12. Dixon MJ, Gazzard J, Chaudhry SS, Sampson N, Schulte BA, Steel KP. Mutation of the Na-K-Cl co-transporter gene Slc12a2 results in deafness in mice. Hum Mol Genet. 1999;8:1579–84.

    Article  CAS  Google Scholar 

  13. Flagella M, Clarke LL, Miller ML, Erway LC, Giannella RA, Andringa A. et al. Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf. J Biol Chem. 1999;274:26946–55.

    Article  CAS  Google Scholar 

  14. Young SZ, Taylor MM, Wu S, Ikeda-Matsuo Y, Kubera C, Bordey A. NKCC1 knockdown decreases neuron production through GABA(A)-regulated neural progenitor proliferation and delays dendrite development. J Neurosci. 2012;32:13630–8.

    Article  CAS  Google Scholar 

  15. Marchese M, Valvo G, Moro F, Sicca F, Santorelli FM. Targeted gene resequencing (astrochip) to explore the tripartite synapse in autism-epilepsy phenotype with macrocephaly. Neuromolecular Med. 2016;18:69–80.

    Article  CAS  Google Scholar 

  16. Merner ND, Mercado A, Khanna AR, Hodgkinson A, Bruat V, Awadalla P. et al. Gain-of-function missense variant in SLC12A2, encoding the bumetanide-sensitive NKCC1 cotransporter, identified in human schizophrenia. J Psychiatr Res. 2016;77:22–6.

    Article  Google Scholar 

  17. Delpire E, Wolfe L, Flores B, Koumangoye R, Schornak CC, Omer S. et al. A patient with multisystem dysfunction carries a truncation mutation in human SLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1. Cold Spring Harb Mol Case Stud. 2016;2:a001289

    Article  Google Scholar 

  18. Anazi S, Maddirevula S, Salpietro V, Asi YT, Alsahli S, Alhashem A. et al. Expanding the genetic heterogeneity of intellectual disability. Hum Genet. 2017;136:1419–29.

    Article  Google Scholar 

  19. Macnamara EF, Koehler AE, D’Souza P, Estwick T, Lee P, Vezina G. et al. Kilquist syndrome: a novel syndromic hearing loss disorder caused by homozygous deletion of SLC12A2. Hum Mutat. 2019;40:532–8.

    Article  CAS  Google Scholar 

  20. Alhebbi H, Peer-Zada AA, Al-Hussaini AA, Algubaisi S, Albassami A, AlMasri N, et al. New paradigms of USP53 disease: normal GGT cholestasis, BRIC, cholangiopathy, and responsiveness to rifampicin. J Hum Genet. 2020;66:151–9.

  21. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  Google Scholar 

  22. Mutai H, Wasano K, Momozawa Y, Kamatani Y, Miya F, Masuda S. et al. Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans. PLoS Genet. 2020;16:e1008643

    Article  CAS  Google Scholar 

  23. Clayton GH, Owens GC, Wolff JS, Smith RL. Ontogeny of cation-Cl- cotransporter expression in rat neocortex. Brain Res Dev Brain Res. 1998;109:281–92.

    Article  CAS  Google Scholar 

  24. Hubner CA, Stein V, Hermans-Borgmeyer I, Meyer T, Ballanyi K, Jentsch TJ. Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. Neuron. 2001;30:515–24.

    Article  CAS  Google Scholar 

  25. Pfeffer CK, Stein V, Keating DJ, Maier H, Rinke I, Rudhard Y. et al. NKCC1-dependent GABAergic excitation drives synaptic network maturation during early hippocampal development. J Neurosci. 2009;29:3419–30.

    Article  CAS  Google Scholar 

  26. Tao R, Li C, Newburn EN, Ye T, Lipska BK, Herman MM. et al. Transcript-specific associations of SLC12A5 (KCC2) in human prefrontal cortex with development, schizophrenia, and affective disorders. J Neurosci. 2012;32:5216–22.

    Article  CAS  Google Scholar 

  27. Callicott JH, Feighery EL, Mattay VS, White MG, Chen Q, Baranger DA. et al. DISC1 and SLC12A2 interaction affects human hippocampal function and connectivity. J Clin Invest. 2013;123:2961–4.

    Article  CAS  Google Scholar 

  28. Gagnon KB, Delpire E. Physiology of SLC12 transporters: lessons from inherited human genetic mutations and genetically engineered mouse knockouts. Am J Physiol Cell Physiol. 2013;304:C693–714.

    Article  Google Scholar 

  29. Sun Q, Tian E, Turner RJ, Ten, Hagen KG. Developmental and functional studies of the SLC12 gene family members from Drosophila melanogaster. Am J Physiol Cell Physiol. 2010;298:C26–37.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the study families for their participation. The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through project number 821.

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Authors and Affiliations

  1. Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia

    Monis Bilal Shamsi, Essa Alharby & Naif A. M. Almontashiri

  2. Section of Medical Genetics, Children’s Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia

    Mohamed Saleh, Ali Alasmari & Eissa A. Faqeih

  3. Department of Medical Imaging, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

    Makki Almuntashri

  4. Molecular Pathology, Pathology and Clinical Laboratory Medicine Administration, King Fahad Medical City, Riyadh, Saudi Arabia

    Manar Samman

  5. Department of Laboratory Medicine, Boston Children’s Hospital, Boston, MA, USA

    Roy W. A. Peake

  6. Unit of Genetic Diseases, Department of Pediatrics, Maternity and Children’s Hospital, Almadinah Almunwarah, Saudi Arabia

    Fatima M. Al-Fadhli

  7. Faculty of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia

    Naif A. M. Almontashiri

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  1. Monis Bilal Shamsi
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Correspondence to Naif A. M. Almontashiri.

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Bilal Shamsi, M., Saleh, M., Almuntashri, M. et al. Clinical characterization and further confirmation of the autosomal recessive SLC12A2 disease. J Hum Genet 66, 689–695 (2021). https://doi.org/10.1038/s10038-021-00904-2

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