To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder.
A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization.
Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons.
Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.
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The TMEM222 variant data were submitted to LOVD database (https://www.lovd.nl/TMEM222) hosted at Leiden University Medical Center, the Netherlands. Accession numbers are available in Table 1. Additional data and materials, such as primer sequences and Sanger sequencing electropherograms, are available upon request.
American Psychiatric Association. Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. 4th ed. (American Psychiatric Association, Washington, DC, 1994).
Leonard, H. & Wen, X. The epidemiology of mental retardation: challenges and opportunities in the new millennium. Ment. Retard. Dev. Disabil. Res. Rev. 8, 117–134, https://doi.org/10.1002/mrdd.10031 (2002).
Ropers, H. H. & Hamel, B. C. X-linked mental retardation. Nat. Rev. Genet. 6, 46–57, https://doi.org/10.1038/nrg1501 (2005).
Maulik, P. K., Mascarenhas, M. N., Mathers, C. D., Dua, T. & Saxena, S. Prevalence of intellectual disability: a meta-analysis of population-based studies. Res. Dev. Disabil. 32, 419–436, https://doi.org/10.1016/j.ridd.2010.12.018 (2011).
Colantuoni, C., Purcell, A. E., Bouton, C. M. & Pevsner, J. High throughput analysis of gene expression in the human brain. J. Neurosci. Res. 59, 1–10 (2000).
Naumova, O. Y. U., Lee, M., Rychkov, S. Y. U., Vlasova, N. V. & Grigorenko, E. L. Gene expression in the human brain: the current state of the study of specificity and spatio-temporal dynamics. Child Dev. 84, 76–88, https://doi.org/10.1111/cdev.12014 (2013).
Musante, L. & Ropers, H. H. Genetics of recessive cognitive disorders. Trends Genet. 30, 32–39, https://doi.org/10.1016/j.tig.2013.09.008 (2014).
van Bokhoven, H. Genetic and epigenetic networks in intellectual disabilities. Annu. Rev. Genet. 45, 81–104, https://doi.org/10.1146/annurev-genet-110410-132512 (2011).
Jamra, R. Genetics of autosomal recessive intellectual disability. Med. Genet. 30, 323–327, https://doi.org/10.1007/s11825-018-0209-z (2018).
Ellison, J. W., Rosenfeld, J. A. & Shaffer, L. G. Genetic basis of intellectual disability. Annu. Rev. Med. 64, 441–450, https://doi.org/10.1146/annurev-med-042711-140053 (2013).
Riazuddin, S. et al. Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability. Mol. Psychiatry 22, 1604–1614, https://doi.org/10.1038/mp.2016.109 (2017).
Kochinke, K. et al. Systematic phenomics analysis deconvolutes genes mutated in intellectual disability into biologically coherent modules. Am. J. Hum. Genet. 98, 149–164, https://doi.org/10.1016/j.ajhg.2015.11.024 (2016).
Antonarakis, S. E. Carrier screening for recessive disorders. Nat. Rev. Genet. 20, 549–561, https://doi.org/10.1038/s41576-019-0134-2 (2019).
Bamshad, M. J., Nickerson, D. A. & Chong, J. X. Mendelian gene discovery: fast and furious with no end in sight. Am. J. Hum. Genet. 105, 448–455, https://doi.org/10.1016/j.ajhg.2019.07.011 (2019).
Hamamy, H. et al. Consanguineous marriages, pearls and perils: Geneva International Consanguinity Workshop Report. Genet. Med. 13, 841–847, https://doi.org/10.1097/GIM.0b013e318217477f (2011).
Schmit, K. & Michiels, C. TMEM proteins in cancer: a review. Front. Pharmacol. 9, 1345, https://doi.org/10.3389/fphar.2018.01345 (2018).
Wrzesiński, T., Szelag, M. & Cieślikowski, W. A. et al. Expression of pre-selected TMEMs with predicted ER localization as potential classifiers of ccRCC tumors. BMC Cancer. 15, 518, https://doi.org/10.1186/s12885-015-1530-4 (2015).
Aruga, J. & Mikoshiba, K. Identification and characterization of Slitrk, a novel neuronal transmembrane protein family controlling neurite outgrowth. Mol. Cell. Neurosci. 24, 117–129 (2003).
Yuan, J. P., Zeng, W., Dorwart, M. R., Choi, Y.-J., Worley, P. F. & Muallem, S. SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nat. Cell. Biol. 11, 337–343, https://doi.org/10.1038/ncb1842 (2009).
Foulquier, F. et al. TMEM165 deficiency causes a congenital disorder of glycosylation. Am. J. Hum. Genet. 91, 15–26, https://doi.org/10.1016/j.ajhg.2012.05.002 (2012).
Brady, O. A., Zheng, Y., Murphy, K., Huang, M. & Hu, F. The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum. Mol. Genet. 22, 685–695, https://doi.org/10.1093/hmg/dds475 (2013).
El-Gebali, S. et al. The Pfam protein families database in 2019. Nucleic Acids Res 47, D427–D432, https://doi.org/10.1093/nar/gky995 (2019).
Sobreira, N., Schiettecatte, F., Valle, D. & Hamosh, A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum. Mutat. 36, 928–930, https://doi.org/10.1002/humu.22844 (2015).
de Brouwer, A. P. M., van Bokhoven, H. & Kremer, H. Comparison of 12 reference genes for normalization of gene expression levels in Epstein-Barr virus-transformed lymphoblastoid cell lines and fibroblasts. Mol. Diagn. Ther. 10, 197–204, https://doi.org/10.1007/BF03256458 (2006).
Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T]) method. Methods. 25, 402–408, https://doi.org/10.1006/meth.2001.1262 (2001).
Frega, M., van Gestel, S. H. C. & Linda, K. et al. Rapid neuronal differentiation of induced pluripotent stem cells for measuring network activity on micro-electrode arrays. J. Vis. Exp. 8, 54900, https://doi.org/10.3791/54900 (2017).
Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J. & Kircher, M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 47, D886–D894, https://doi.org/10.1093/nar/gky1016 (2019).
Genome Aggregation Database Consortium, KarczewskiK. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 581, 434–443, https://doi.org/10.1038/s41586-020-2308-7 (2020).
GTex Consortium. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585, https://doi.org/10.1038/ng.2653 (2013).
Nakai, K. & Horton, P. PSORT: a program for detecting sorting signals in proteins and predicting their subcellular localization. Trends Biochem. Sci. 24, 34–36 (1999).
Frischmeyer, P. A. & Dietz, H. C. Nonsense-mediated mRNA decay in health and disease. Hum. Mol. Genet. 8, 1893–1900, https://doi.org/10.1093/hmg/8.10.1893 (1999).
Maquat, L. E. When cells stop making sense: effects of nonsense codons on RNA metabolism in vertebrate cells. RNA. 1, 453–465 (1995).
UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res. 47, D506–D515, https://doi.org/10.1093/nar/gky1049 (2019).
Klaassen, R. V. et al. Shisa6 traps AMPA receptors at postsynaptic sites and prevents their desensitization during synaptic activity. Nat. Commun. 7, 10682, https://doi.org/10.1038/ncomms10682 (2016).
Vandervore, L. V. et al. TMX2 is a crucial regulator of cellular redox state, and its dysfunction causes severe brain developmental abnormalities. Am. J. Hum. Genet. 105, 1126–1147, https://doi.org/10.1016/j.ajhg.2019.10.009 (2019).
Agbaga, M.-P., Brush, R. S., Mandal, M. N. A., Henry, K., Elliott, M. H. & Anderson, R. E. Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids. Proc. Natl. Acad. Sci. U. S. A. 105, 12843–12848, https://doi.org/10.1073/pnas.0802607105 (2008).
Aldahmesh, M. A. et al. Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia. Am. J. Hum. Genet. 89, 745–750, https://doi.org/10.1016/j.ajhg.2011.10.011 (2011).
Cadieux-Dion, M. et al. Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia. JAMA Neurol. 71, 470, https://doi.org/10.1001/jamaneurol.2013.6337 (2014).
Sievers, F. et al. Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega. Mol. Syst. Biol. 7, 539, https://doi.org/10.1038/msb.2011.75 (2011).
We are grateful to the families who have participated in this study. This work was supported the EU FP7 Large-Scale Integrating Project Genetic and Epigenetic Networks in Cognitive Dysfunction (241995) (to H.v.B.), an ERC grant (to S.E.A.), National Institute on Neurological Disorders and Stroke (R01NS107428) (to Sheikh Riazuddin), the National Institute of Neurological Disorders and Stroke (NINDS) under award number K08NS092898, Jordan’s Guardian Angels and the Brotman Baty Institute (to G.M.M.) and state assignment of Ministry of Science and Higher Education of the Russian Federation for RCMG. D.L.P. is recipient of a CAPES Fellowship (99999.013311/2013-01). Part of this work was supported by Higher Education Commission of Pakistan (NRPU project number 10700 to M.S.).
Individuals were identified in different centers worldwide in diagnostic or research settings approved by the respective institutional review boards: the Institutional Review Board Commissie Mensgebonden Onderzoek Regio Arnhem-Nijmegen, the Netherlands; Institutional Review Board at University of Maryland School of Medicine, Baltimore, Maryland, USA; Institutional Review Board, Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan; Institution Board of Jordan University Hospital, Amman, Jordan; Bioethics Committee of the University Hospitals and the Canton of Geneva, Switzerland; Ethics Committee of the Research Centre for Medical Genetics, Moscow, Russia; Persian BayanGene Research and Training Center Ethics Committee, Shiraz, Iran; institutional review boards of the Hanover Medical School the Children’s and Youth Hospital Auf der Bul, Hannover, Germany. Written informed consents were obtained from all the participating adults and guardians of affected individuals. Specific written informed consent was obtained for publishing the patients’ photographs. This study adhered to the World Medical Association Declaration of Helsinki (2013).
The authors declare no competing interests.
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Polla, D.L., Farazi Fard, M.A., Tabatabaei, Z. et al. Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder. Genet Med (2021). https://doi.org/10.1038/s41436-021-01133-w