NTNG2 Mutation: A candidate gene for a new brain-skin disorder with early neuropsychiatric manifestation? An analysis based on 3000 patients

Yıl 2022, , 93 - 99, 27.03.2022

Akif Ayaz , Burak Yuluğ

https://doi.org/10.30565/medalanya.1086508

Öz

Aim: In this study, the relationship between genetic analysis and exome sequencing and clinical and neuroimaging findings of four patients from the same family was investigated by analyzing a clinical and genetic (WES) database containing more than 3000 patients.

Methods: We analyzed the WES data of approximately 3000 patients performed in our center in terms of NTNG2 biallelic mutations. In addition, MR imaging findings were investigated.

Results: We found four patients with the same mutation in the NTNG2 gene, presenting with similar clinical and neuroimaging findings. As a result of filtering, the c.242G>A variant was determined in the NTNG2 gene. In addition, mild to severe brain parenchymal volume loss and frontal and temporal lobe atrophy were seen in cases 1, 2, and 4 on axial T2-weighted MRI.

Conclusion: The current study has similar phenotypic and genotypic features and is a very rare report showing NTNG2 mutation in this context. Existing clinical data are important in choosing NTNG2 gene-related neuropsychiatric disorders as a future treatment target.

Anahtar Kelimeler

Netrin-g2; Synapse formation, Phenotype, WES analysis, Schizophrenia, Neuropsychiatric Disease

NTNG2 Mutasyonu: Erken nöropsikiyatrik manifestasyonlu yeni bir beyin-cilt hastalığı için aday bir gen mi? 3000 hasta üzerinden bir analiz.

Öz

Amaç: Bu çalışmada 3000'den fazla hastayı içeren klinik ve genetik (WES) veri tabanını analiz ederek aynı aileden dört hastanın genetik analizi ve ekzom dizilimi ile klinik ve nörogörüntüleme bulguları arasındaki ilişki araştırılmıştır.

Yöntem: Merkezimizde 3000 hastanın WES verileri NTNG2 bialelik mutasyonları açısından incelendi. Ayrıca MR görüntüleme bulguları araştırıldı.

Bulgular: NTNG2 geninde aynı mutasyona sahip, benzer klinik ve nörogörüntüleme bulguları ile başvuran dört hasta bulundu. Filtreleme sonucunda NTNG2 geninde c.242G>A varyantı belirlendi. Ayrıca aksiyel T2 ağırlıklı MRG'de vaka 1, 2 ve 4'te hafif ila şiddetli beyin parankimal hacim kaybı ve frontal ve temporal lob atrofisi görüldü.

Sonuç: Mevcut çalışma benzer fenotipik ve genotipik özelliklere sahip olup bu bağlamda NTNG2 mutasyonunu gösteren çok nadir bir rapordur. Mevcut klinik data NTNG2 geniyle ilişkili nöropsikiyatrik bozukluklarda gelecekteki bir tedavi hedefi olarak seçilmesinde öneme sahiptir.

Anahtar Kelimeler

Netrin-g2, Sinaps oluşumu, Fenotip, WES analizi, Şizofreni, Nöropsikiyatrik hastalık

Kaynakça

• 1. Nakashiba T, Nishimura S, Ikeda T, Itohara S. Complementary expression and neurite outgrowth activity of netrin-G subfamily members. Mech Dev. 2002;111(1-2):47-60. doi: 10.1016/s0925-4773(01)00600-1.
• 2. Nakashiba T, Ikeda T, Nishimura S, Tashiro K, Honjo T, Culotti JG, Itohara S. Netrin-G1: a novel glycosyl phosphatidylinositol-linked mammalian netrin that is functionally divergent from classical netrins. J Neurosci. 2000;20(17):6540-50. doi: 10.1523/JNEUROSCI.20-17-06540.2000.
• 3. Yin Y, Miner JH, Sanes JR. Laminets: laminin- and netrin-related genes expressed in distinct neuronal subsets. Mol Cell Neurosci. 2002;19(3):344-58. doi: 10.1006/mcne.2001.1089.
• 4. Lin JC, Ho WH, Gurney A, Rosenthal A. The netrin-G1 ligand NGL-1 promotes the outgrowth of thalamocortical axons. Nat Neurosci. 2003;6(12):1270-6. doi: 10.1038/nn1148.
• 5. Kim S, Burette A, Chung HS, Kwon SK, Woo J, Lee HW, Kim K, Kim H, Weinberg RJ, Kim E. NGL family PSD-95-interacting adhesion molecules regulate excitatory synapse formation. Nat Neurosci. 2006;9(10):1294-301. doi: 10.1038/nn1763.
• 6. Zhang W, Rajan I, Savelieva KV, Wang CY, Vogel P, Kelly M, Xu N, Hasson B, Jarman W, Lanthorn TH. Netrin-G2 and netrin-G2 ligand are both required for normal auditory responsiveness. Genes Brain Behav. 2008;7(4):385-92. doi: 10.1111/j.1601-183X.2007.00361.x.
• 7. Eastwood SL, Harrison PJ. Decreased mRNA expression of netrin-G1 and netrin-G2 in the temporal lobe in schizophrenia and bipolar disorder. Neuropsychopharmacology. 2008;33(4):933-45. doi: 10.1038/sj.npp.1301457
• 8. Aoki-Suzuki M, Yamada K, Meerabux J, Iwayama-Shigeno Y, Ohba H, Iwamoto K, Takao H, Toyota T, Suto Y, Nakatani N, Dean B, Nishimura S, Seki K, Kato T, Itohara S, Nishikawa T, Yoshikawa T. A family-based association study and gene expression analyses of netrin-G1 and -G2 genes in schizophrenia. Biol Psychiatry. 2005 Feb 15;57(4):382-93. doi: 10.1016/j.biopsych.2004.11.022.
• 9. Fukasawa M, Aoki M, Yamada K, Iwayama-Shigeno Y, Takao H, Meerabux J, Toyota T, Nishikawa T, Yoshikawa T. Case-control association study of human netrin G1 gene in Japanese schizophrenia. J Med Dent Sci. 2004 Jun;51(2):121-8. PMID: 15508520.
• 10. Harrison PJ, Owen MJ. Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet. 2003 Feb 1;361(9355):417-9. doi: 10.1016/S0140-6736(03)12379-3.
• 11. Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10(1):40-68; image 5. doi: 10.1038/sj.mp.4001558.
• 12. Wei G, Deng X, Agarwal S, Iwase S, Disteche C, Xu J. Patient Mutations of the Intellectual Disability Gene KDM5C Downregulate Netrin G2 and Suppress Neurite Growth in Neuro2a Cells. J Mol Neurosci. 2016;60(1):33-45. doi: 10.1007/s12031-016-0770-3.
• 13. Holmén A, Juuhl-Langseth M, Thormodsen R, Ueland T, Agartz I, Sundet K, Andreassen OA, Rund BR, Melle I. Executive function in early- and adult onset schizophrenia. Schizophr Res. 2012;142(1-3):177-82. doi: 10.1016/j.schres.2012.10.006.
• 14. Wong AH, Van Tol HH. Schizophrenia: from phenomenology to neurobiology. Neurosci Biobehav Rev. 2003;27(3):269-306. doi: 10.1016/s0149-7634(03)00035-6.
• 15. Aydın E, Cansu Ülgen M, Tabo A, Devrim Balaban Ö, Yeşilyurt S, Yumrukçal H. Executive function and genetic loading in nonpsychotic relatives of schizophrenia patients. Psychiatry Res. 2017;248:105-110. doi: 10.1016/j.psychres.2016.12.027.
• 16. Erol A, Bayram S, Kosger F, Mete L. Executive functions in patients with familial versus sporadic schizophrenia and their parents. Neuropsychobiology. 2012;66(2):93-9. doi: 10.1159/000337738.
• 17. Bunney WE, Bunney BG. Evidence for a compromised dorsolateral prefrontal cortical parallel circuit in schizophrenia. Brain Res Brain Res Rev. 2000;31(2-3):138-46. doi: 10.1016/s0165-0173(99)00031-4.
• 18. DL, Geyer MA. Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry. 1990;47(2):181-8. doi: 10.1001/archpsyc.1990.01810140081011.
• 19. Woo J, Kwon SK, Kim E. The NGL family of leucine-rich repeat-containing synaptic adhesion molecules. Mol Cell Neurosci. 2009 Sep;42(1):1-10. doi: 10.1016/j.mcn.2009.05.008.