BTBD9 explained

BTB domain containing 9 is a protein that in humans is encoded by the BTBD9 gene.

BTBD9 is in a subgroup of BTB(POZ) proteins, which contribute to the forming of limbs and determination of cell fate in developing Drosophila melanogaster.^[1] BTB(POZ) proteins also play a role in cellular functions such as: cytoskeleton regulation, transcription regulation, the gating and assembly of ion channels, and ubiquitination of proteins. BTBD9 is highly expressed throughout the brain and shows variable levels of expression in most other body tissues.^{[2] [3]}

The gene is located on the short arm of chromosome 6 and the domain contains eight exons and seven introns. The chromosome 6 locational domain that codes for BTB(POZ) proteins is understood to contain genes encoding protein-protein interactions.^[4] BTBD9 is a protein located in cellular cytosol and also expressed within Human embryonic kidney cell lineages. There is also evidence suggesting that BTBD9 is highly expressed within the human nervous system from comparison analysis to Drosophila and human cell studies.

Animal models

There are extensive homologs to BTBD9 which allow for the use of animal models in deciphering its functions and interactions. The BTBD9 homolog Btbd9 is extensively expressed in the central nervous system of adult mice including the thalamus, sub-thalamic nuclei, cerebral cortex, cerebellum, hippocampus, and caudate nucleus.^[5] The Drosophila homolog dBTBD9, was shown to regulate dopamine levels in the Drosophila brain and iron regulation in human cell-lines.^[6]

Synaptic plasticity

A recent study using Btbd9 knockout mice argued that BTBD9 is involved in synaptic plasticity, learning and memory, and protein alterations associated with vesicle recycling and endocytosis.^[7]

Clinical relevance

There is some evidence that BTBD9 may be associated with Restless legs syndrome. However, there is not a known mutation of the BTBD9 gene that is responsible for the onset of the RLS.^[8] Mutations to BTBD9 are positively correlated with characteristic symptoms of Restless leg syndrome such as decreased dopamine levels, increased movement, and disrupted sleep patterns. The overrepresentation of single nucleotide polymorphisms expressed in BTBD9 may be associated with Restless legs syndrome and nighttime leg movements. Single nucleotide polymorphisms in BTBD9 that have been linked to Restless leg syndrome are also correlated with Tourette’s Syndrome that doesn’t present with Obsessive Compulsive Disorder.^[9] One scientific review regarding Restless Legs Syndrome expressed that Restless Legs Syndrome is a complex syndrome that has many risk factor indicators including the presence of the BTBD9 gene.^[10] Drosophila CG18126 gene loss was found to be correlated to sleep lost behavior within fruit fly experiments. The BTBD9 gene through the use of iron regulatory protein-2 in human cell line is found to be associated with the regulation of iron levels in human cells. One scientific review discussed how the iron level association found in human cell lines was also present in animal phenotypes.^[10] These model organisms could have normal iron levels present throughout the body even when the dopamine neural pathways had below normal iron levels within the brain due to the BTBD9 presence. One study was able to look at a single nucleotide polymorphism in BTBD9. This mutation can be contributed to these various health issues.^[11] The BTBD9 gene has also been linked to blood anemia in a study.^[12] The study linked a genetic marker in the BTBD9 gene with anemia in blood donors. It was found that higher ferritin levels could be connected to a variant in the allele (G) in the BTBD9 gene. The study was only conducted with Australian blood donors. The high ferritin levels indicated a contribution to the variant allel (G) while decreased ferritin levels indicate the BTBD9 gene is being over expressed.^[12]

Notes and References

1. Stogios PJ, Downs GS, Jauhal JJ, Nandra SK, Privé GG . Sequence and structural analysis of BTB domain proteins . Genome Biology . 6 . 10 . R82 . 15 September 2005 . 16207353 . 1257465 . 10.1186/gb-2005-6-10-r82 . free .
2. Web site: Gene: BTBD9 - ENSG00000183826. bgee.org. en. 2020-04-14.
3. Web site: BTBD9 BTB domain containing 9 [Homo sapiens (human)] - Gene - NCBI]. 2021-11-13. www.ncbi.nlm.nih.gov.
4. Web site: BTBD9 gene . November 26, 2019. U.S. National Library of Medicine. live. https://web.archive.org/web/20150313035210/http://ghr.nlm.nih.gov:80/gene/BTBD9 . 2015-03-13 . December 2, 2019.
5. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ, Chen L, Chen L, Chen TM, Chin MC, Chong J, Crook BE, Czaplinska A, Dang CN, Datta S, Dee NR, Desaki AL, Desta T, Diep E, Dolbeare TA, Donelan MJ, Dong HW, Dougherty JG, Duncan BJ, Ebbert AJ, Eichele G, Estin LK, Faber C, Facer BA, Fields R, Fischer SR, Fliss TP, Frensley C, Gates SN, Glattfelder KJ, Halverson KR, Hart MR, Hohmann JG, Howell MP, Jeung DP, Johnson RA, Karr PT, Kawal R, Kidney JM, Knapik RH, Kuan CL, Lake JH, Laramee AR, Larsen KD, Lau C, Lemon TA, Liang AJ, Liu Y, Luong LT, Michaels J, Morgan JJ, Morgan RJ, Mortrud MT, Mosqueda NF, Ng LL, Ng R, Orta GJ, Overly CC, Pak TH, Parry SE, Pathak SD, Pearson OC, Puchalski RB, Riley ZL, Rockett HR, Rowland SA, Royall JJ, Ruiz MJ, Sarno NR, Schaffnit K, Shapovalova NV, Sivisay T, Slaughterbeck CR, Smith SC, Smith KA, Smith BI, Sodt AJ, Stewart NN, Stumpf KR, Sunkin SM, Sutram M, Tam A, Teemer CD, Thaller C, Thompson CL, Varnam LR, Visel A, Whitlock RM, Wohnoutka PE, Wolkey CK, Wong VY, Wood M, Yaylaoglu MB, Young RC, Youngstrom BL, Yuan XF, Zhang B, Zwingman TA, Jones AR . Genome-wide atlas of gene expression in the adult mouse brain . Nature . 445 . 7124 . 168–176 . January 2007 . 17151600 . 10.1038/nature05453 . 4421492 . 2007Natur.445..168L .
6. Freeman A, Pranski E, Miller RD, Radmard S, Bernhard D, Jinnah HA, Betarbet R, Rye DB, Sanyal S . Sleep fragmentation and motor restlessness in a Drosophila model of Restless Legs Syndrome . Current Biology . 22 . 12 . 1142–1148 . June 2012 . 22658601 . 3381864 . 10.1016/j.cub.2012.04.027 . 2012CBio...22.1142F .
7. DeAndrade MP, Zhang L, Doroodchi A, Yokoi F, Cheetham CC, Chen HX, Roper SN, Sweatt JD, Li Y . Enhanced hippocampal long-term potentiation and fear memory in Btbd9 mutant mice . PLOS ONE . 7 . 4 . e35518 . 2012 . 22536397 . 3334925 . 10.1371/journal.pone.0035518 . Di Cunto F . free . 2012PLoSO...735518D .
8. Zhang L, Fu YH . The molecular genetics of human sleep . The European Journal of Neuroscience . 51 . 1 . 422–428 . January 2020 . 30144347 . 6389443 . 10.1111/ejn.14132 .
9. Rivière JB, Xiong L, Levchenko A, St-Onge J, Gaspar C, Dion Y, Lespérance P, Tellier G, Richer F, Chouinard S, Rouleau GA . Association of intronic variants of the BTBD9 gene with Tourette syndrome . Archives of Neurology . 66 . 10 . 1267–1272 . October 2009 . 19822783 . 10.1001/archneurol.2009.213 . free .
10. Allen RP, Donelson NC, Jones BC, Li Y, Manconi M, Rye DB, Sanyal S, Winkelmann J . Animal models of RLS phenotypes . Sleep Medicine . 31 . 23–28 . March 2017 . 27839945 . 5349858 . 10.1016/j.sleep.2016.08.002 . Advances in Scientific Understanding of the Restless Legs Syndrome (RLS) (aka: Willis Ekbom Disease (WED)) .
11. Ji Y, Flower R, Hyland C, Saiepour N, Faddy H . Genetic factors associated with iron storage in Australian blood donors . Blood Transfusion = Trasfusione del Sangue . 16 . 2 . 123–129 . February 2018 . 28151393 . 5839608 . 10.2450/2016.0138-16 .
12. DeAndrade MP, Johnson RL, Unger EL, Zhang L, van Groen T, Gamble KL, Li Y . Motor restlessness, sleep disturbances, thermal sensory alterations and elevated serum iron levels in Btbd9 mutant mice . Human Molecular Genetics . 21 . 18 . 3984–3992 . September 2012 . 22678064 . 3428151 . 10.1093/hmg/dds221 .