Welcome to our NKX6-2 publication library. We aim to keep this collection as complete as possible, adding new research as soon as it's published. We hope this resource serves as a valuable tool for everyone on the NKX6-2 journey.
Clinical and Genetic Studies of NKX6-2 Related Disorders
Fundamental Biology and Function of the NKX6-2 Gene and its Protein Product
Clinical and Genetic Studies of NKX6-2 Related Disorders
This section includes publications that focus on identifying and characterizing human genetic disorders, such as spastic ataxia 8 (SPAX8) and hypomyelinating leukodystrophy, caused by mutations in the NKX6-2 gene. These studies describe patient phenotypes, neuroimaging findings, and the genetic variants responsible for the conditions.
NKX6-2 Disease in Two Unrelated Patients with Early-Onset Spastic Quadriplegia and Diffuse Hypomyelinating Leukodystrophy
2023
This paper describes two unrelated children with a severe, inherited brain disorder that causes stiffness and developmental problems, linking their condition to new errors found in the NKX6-2 gene.
Shurrab S, Cordeiro D, Mercimek-Andrews S, Shuen AY. NKX6-2 Disease in Two Unrelated Patients with Early-Onset Spastic Quadriplegia and Diffuse Hypomyelinating Leukodystrophy. Brain Disorders. 2023;9:100069.
Hypomyelinating leukodystrophy – NKX6-2 gene variant as a cause
2021
This report details the case of a teenager whose brain didn't develop enough protective myelin coating, causing severe physical and developmental issues, and traces the cause to a specific error in his NKX6-2 gene.
Guder P, Lobel U, Fiebig B, Oppermann I, Berger A, Bley A. Hypomyelinating leukodystrophy – NKX6-2 gene variant as a cause. Brain Disorders. 2020;2:100006.
A homozygous missense variant in the homeobox domain of the NKX6-2 results in progressive spastic ataxia type 8 associated with lower limb weakness and neurological manifestations
2020
This study investigates a large family where several members suffer from a progressive disorder causing muscle stiffness and unsteadiness, identifying a new genetic error in the NKX6-2 gene as the cause.
Almatrafi A, Umair M, Eldardear A, Al-Luqmani M, Hashmi JA, Albalawi AM, Alfadhel M, Ramzan K, Basit S. A homozygous missense variant in the homeobox domain of the NKX6-2 results in progressive spastic ataxia type 8 associated with lower limb weakness and neurological manifestations. J Gene Med. 2020;22(8):e3196.
Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination
2020
This paper presents 11 new cases of a brain disorder caused by errors in the NKX6-2 gene, showing that the condition can range from very severe in newborns to a milder form that appears in childhood.
Chelban V, Alsagob M, Kloth K, Chirita-Emandi A, Vandrovcova J, Maroofian R, Davagnanam I, Bakhtiari S, AlSayed MD, Rahbeeni Z, AlZaidan H, Malintan NT, Johannsen J, Efthymiou S, Ghayoor Karimiani E, Mankad K, Al-Shahrani SA, Beiraghi Toosi M, AlShammari M, Groppa S, Haridy NA, AlQuait L, Qari A, Huma R, Salih MA, Almass R, Almutairi FB, Hamad MH, Alorainy IA, Ramzan K, Imtiaz F, Puiu M, Kruer MC, Bierhals T, Wood NW, Colak D, Houlden H, Kaya N. Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination. Eur J Neurol. 2020;27(2):334-342.
Expanding the clinical and neuroimaging features of NKX6-2-related hereditary spastic ataxia type 8
2020
This study describes two siblings with a disorder causing developmental delays and stiffness and is the first to discover that errors in the NKX6-2 gene can also cause nerve damage in the arms and legs.
Hosseini Bereshneh A, Hosseipour S, Rasoulinezhad MS, Pak N, Garshasbi M, Tavasoli AR. Expanding the clinical and neuroimaging features of NKX6-2-related hereditary spastic ataxia type 8. Eur J Med Genet. 2020;63(5):103868.
Expanding the clinical and genetic spectra of NKX6-2-related disorder
2018
This report provides definitive proof that errors in the NKX6-2 gene cause a brain disorder by studying six new families, adding seizures and developmental regression to the list of known symptoms.
Baldi C, Bertoli-Avella AM, Al-Sannaa N, Alfadhel M, Al-Thihli K, Alameer S, Elmonairy AA, Al Shamsi AM, Abdelrahman HA, Al-Gazali L, Shawli A, Al-Hakami F, Yavuz H, Kandaswamy KK, Rolfs A, Brandau O, Bauer P. Expanding the clinical and genetic spectra of NKX6-2-related disorder. Clin Genet. 2018;93(5):1087-1092.
NKX6-2-Related Disorder
2018
This document provides a comprehensive overview of the disorder caused by the NKX6-2 gene, describing its range of symptoms, how it is diagnosed, and how it can be managed.
Chelban V, Kaya N, Alkuraya F, Houlden H. NKX6-2-Related Disorder. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993. 2018 Oct 4.
NKX6-2-Related Disorder
2018
This document provides a comprehensive overview of the disorder caused by the NKX6-2 gene, describing its range of symptoms, how it is diagnosed, and how it can be managed.
Chelban V, Kaya N, Alkuraya F, Houlden H. NKX6-2-Related Disorder. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993. 2018 Oct 4.
Expanding the genetic heterogeneity of intellectual disability
2017
This broad study of intellectual disability confirms that errors in several genes, including NKX6-2, are a cause of the condition.
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. Expanding the genetic heterogeneity of intellectual disability. Hum Genet. 2017;136(11-12):1419-1429.
Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination
2017
This was a key discovery paper that first identified errors in the NKX6-2 gene as the cause of an inherited disorder involving progressive stiffness, unsteadiness, and poor brain insulation by studying three families.
Chelban V, Patel N, Vandrovcova J, Zanetti MN, Lynch DS, Ryten M, Botía JA, Bello O, Tribollet E, Efthymiou S, Davagnanam I; SYNAPSE Study Group; Bashiri FA, Wood NW, Rothman JE, Alkuraya FS, Houlden H. Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination. Am J Hum Genet. 2017;100(6):969-977.
Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy
2017
This study identified that errors in a critical part of the NKX6-2 gene are the cause of a new, severe brain disorder that prevents the protective myelin coating around nerves from forming properly.
Dorboz I, Aiello C, Simons C, Stone RT, Niceta M, Elmaleh M, Abuawad M, Doummar D, Bruselles A, Wolf NI, Travaglini L, Boespflug-Tanguy O, Tartaglia M, Vanderver A, Rodriguez D, Bertini E. Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy. Brain. 2017;140(10):2550-2556.
Fundamental Biology and Function
This section comprises publications focused on the fundamental biology of the NKX6-2 gene and its protein product. These studies use model organisms (mice, zebrafish, frogs) and cell-based systems to investigate its function as a transcription factor, its expression patterns during development, its role in processes like myelination and neurogenesis.
Is spastic ataxia 8 a protein misfolding disorder?
2024
This lab study investigates how different genetic errors cause the NKX6-2 protein to clump together inside cells, suggesting the related brain disorder may be caused by this protein misfolding.
Ferreira-Peralta P, França B, Murtinheira F, Rodrigues MS, Herrera F. Is spastic ataxia 8 a protein misfolding disorder? Biochim Biophys Acta Mol Basis Dis. 2024;1870(1):166882.
Selective dopamine D2 receptor deletion from Nkx6.2 expressing cells causes impaired cognitive, motivation and anxiety phenotypes in mice
2023
This study uses mice to understand which types of brain cells develop from precursors expressing the Nkx6.2 gene and finds that removing a dopamine receptor from these specific cells causes problems with thinking, motivation, and anxiety.
Bechelli L, Tomasella E, Cardoso SL, Belmonte M, Gelman DM. Selective dopamine D2 receptor deletion from Nkx6.2 expressing cells causes impaired cognitive, motivation and anxiety phenotypes in mice. Sci Rep. 2023;13(1):19473.
Keeping IPMNs in Check: A Novel Role for the Transcription Factor NKX6-2 in Preserving an Indolent Cell Identity in Pancreatic Cystic Lesions
2023
This paper shows that NKX6-2 helps keep certain pancreatic growths (IPMNs) in a less dangerous, early stage, giving researchers new clues that could improve how doctors predict risk and develop treatments for pancreatic cancer.
Ben-Shmuel A, Scherz-Shouval R. Keeping IPMNs in Check: A Novel Role for the Transcription Factor NKX6-2 in Preserving an Indolent Cell Identity in Pancreatic Cystic Lesions. Cancer Discov. 2023;13(8):1768-1770.
Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential
2023
This research on pancreatic growths identifies the NKX6-2 gene as a key player in keeping these growths in a less aggressive, or "indolent," state.
Sans M, Makino Y, Min J, Rajapakshe KI, Yip-Schneider M, Schmidt CM, Hurd MW, Burks JK, Gomez JA, Thege FI, Fahrmann JF, Wolff RA, Kim MP, Guerrero PA, Maitra A. Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential. Cancer Discov. 2023;13(8):1844-1861.
One-step Reprogramming of Human Fibroblasts into Oligodendrocyte-like Cells by SOX10, OLIG2, and NKX6.2
2021
This paper develops a new lab technique to rapidly turn human skin cells directly into the brain cells that make myelin by adding a cocktail of three genes, including NKX6.2.
Chanoumidou K, Hernández-Rodríguez B, Windener F, Thomas C, Stehling M, Mozafari S, Albrecht S, Ottoboni L, Antel J, Kim KP, Velychko S, Cui QL, Xu YKT, Martino G, Winkler J, Schöler HR, Baron-Van Evercooren A, Boespflug-Tanguy O, Vaquerizas JM, Ehrlich M, Kuhlmann T. One-step Reprogramming of Human Fibroblasts into Oligodendrocyte-like Cells by SOX10, OLIG2, and NKX6.2. Stem Cell Reports. 2021;16(4):771-783.
Onecut-dependent Nkx6.2 transcription factor expression is required for proper formation and activity of spinal locomotor circuits
2020
This study in mice shows that the Nkx6.2 gene is essential for the proper development and activity of the spinal cord circuits that control walking and movement.
Toch M, Harris A, Schakman O, Kondratskaya E, Boulland JL, Dauguet N, Debrulle S, Baudouin C, Hidalgo-Figueroa M, Mu X, Gow A, Glover JC, Tissir F, Clotman F. Onecut-dependent Nkx6.2 transcription factor expression is required for proper formation and activity of spinal locomotor circuits. Sci Rep. 2020;10(1):996.
Xenopus Nkx6.1 and Nkx6.2 are required for mid-hindbrain boundary development
2013
This study found that two genes, Nkx6.1 and Nkx6.2, are needed to properly shape the area of the brain that develops into the midbrain and cerebellum in frog embryos, because they help turn on signals that guide this part of brain formation.
Ma P, Xia Y, Ma L, Zhao S, Mao B. Xenopus Nkx6.1 and Nkx6.2 are required for mid-hindbrain boundary development. Dev Genes Evol. 2013;223(4):253-259.
Nkx6 genes pattern the frog neural plate and Nkx6.1 is necessary for motoneuron axon projection
2011
This research uses frog embryos to understand how Nkx6 genes help shape the developing nervous system and finds that a related gene, Nkx6.1, is critical for nerves to grow correctly from the spinal cord to the muscles.
Dichmann DS, Harland RM. Nkx6 genes pattern the frog neural plate and Nkx6.1 is necessary for motoneuron axon projection. Dev Biol. 2011;349(2):378-386.
Nkx6.2 synergizes with Cdx-2 in stimulating proglucagon gene expression
2011
This lab study discovers that the Nkx6.2 protein works together with another protein, Cdx-2, to turn on the gene responsible for producing glucagon, a hormone important for controlling blood sugar.
Wang PX, Yu ZW, Wong S, Jin TR. Nkx6.2 synergizes with Cdx-2 in stimulating proglucagon gene expression. World J Diabetes. 2011;2(5):66-74.
Nkx6.1 and nkx6.2 regulate alpha- and beta-cell formation in zebrafish by acting on pancreatic endocrine progenitor cells
2010
This study on zebrafish finds that two related genes, nkx6.1 and nkx6.2, are both needed to create the pancreatic cells that produce glucagon (which raises blood sugar) and are redundantly involved in making insulin-producing cells.
Binot AC, Manfroid I, Flasse L, Winandy M, Motte P, Martial JA, Peers B, Voz ML. Nkx6.1 and nkx6.2 regulate alpha- and beta-cell formation in zebrafish by acting on pancreatic endocrine progenitor cells. Dev Biol. 2010;340(2):397-407.
Co-localization of Nkx6.2 and Nkx2.2 homeodomain proteins in differentiated myelinating oligodendrocytes
2010
This paper studies mouse spinal cords and finds that two important proteins, Nkx6.2 and Nkx2.2, are located together in the mature brain cells that create the protective myelin coating around nerves.
Cai J, Zhu Q, Zheng K, Li H, Qi Y, Cao Q, Qiu M. Co-localization of Nkx6.2 and Nkx2.2 homeodomain proteins in differentiated myelinating oligodendrocytes. Glia. 2010;58(4):458-468.
Dynamic expression patterns of Nkx6.1 and Nkx6.2 in the developing mes-diencephalic basal plate
2010
This research maps out exactly where the Nkx6.1 and Nkx6.2 genes are active in the developing mouse midbrain, suggesting they help build the part of the brain that controls eye movements.
Moreno-Bravo JA, Perez-Balaguer A, Martinez S, Puelles E. Dynamic expression patterns of Nkx6.1 and Nkx6.2 in the developing mes-diencephalic basal plate. Dev Dyn. 2010;239(7):2094-2101.
Characterization of Nkx6-2-derived neocortical interneuron lineages
2009
This study genetically traces the "family tree" of brain cells in mice that come from early cells expressing the Nkx6-2 gene, finding that they produce a wide variety of specialized nerve cells.
Sousa VH, Miyoshi G, Hjerling-Leffler J, Karayannis T, Fishell G. Characterization of Nkx6-2-derived neocortical interneuron lineages. Cereb Cortex. 2009;19 Suppl 1:i1-i10.
Cloning of zebrafish nkx6.2 and a comprehensive analysis of the conserved transcriptional response to Hedgehog/Gli signaling in the zebrafish neural tube
2007
This paper identifies the zebrafish version of the nkx6.2 gene and confirms that it is turned on by a key developmental signal called "Hedgehog," just as it is in other animals.
Guner B, Karlstrom RO. Cloning of zebrafish nkx6.2 and a comprehensive analysis of the conserved transcriptional response to Hedgehog/Gli signaling in the zebrafish neural tube. Gene Expr Patterns. 2007;7(5):595-605.
The transcription factors Nkx6.1 and Nkx6.2 possess equivalent activities in promoting beta-cell fate specification in Pdx1+ pancreatic progenitor cells
2007
This study shows through experiments in mice that two related genes, Nkx6.1 and Nkx6.2, can perform the same job in helping create the insulin-producing cells of the pancreas.
Nelson SB, Schaffer AE, Sander M. The transcription factors Nkx6.1 and Nkx6.2 possess equivalent activities in promoting beta-cell fate specification in Pdx1+ pancreatic progenitor cells. Development. 2007;134(13):2491-2500.
Nkx6 proteins specify one zebrafish primary motoneuron subtype by regulating late islet1 expression
2007
This paper shows that in zebrafish, Nkx6 proteins help shape specific motoneuron subtypes by sustaining Islet1 activity, which is essential for MiP motoneuron identity and for preventing them from turning into interneurons.
Hutchinson SA, Cheesman SE, Hale LA, Boone JQ, Eisen JS. Nkx6 proteins specify one zebrafish primary motoneuron subtype by regulating late islet1 expression. Development. 2007;134(9):1671-1677.
Multiple dorsoventral origins of oligodendrocyte generation in the spinal cord and hindbrain
2005
This research in mice reveals that myelin-making cells (oligodendrocytes) can develop from both the top (dorsal) and bottom (ventral) parts of the spinal cord, and shows that Nkx6 genes are essential for this process in the spinal cord but surprisingly block it in parts of the developing brain.
Vallstedt A, Klos JM, Ericson J. Multiple dorsoventral origins of oligodendrocyte generation in the spinal cord and hindbrain. Neuron. 2005;45(1):55-67.
NKX6 transcription factor activity is required for alpha- and beta-cell development in the pancreas
2005
This research discovers that, contrary to previous understanding, Nkx6 genes are necessary for making both the insulin-producing and the glucagon-producing cells of the pancreas in mice.
Henseleit KD, Nelson SB, Kuhlbrodt K, Hennings JC, Ericson J, Sander M. NKX6 transcription factor activity is required for alpha- and beta-cell development in the pancreas. Development. 2005;132(13):3139-3149.
CNS myelin paranodes require Nkx6-2 homeoprotein transcriptional activity for normal structure
2004
This study finds that mice missing the Nkx6-2 gene have trouble with coordination because the specialized connections between nerves and their protective myelin coating are not formed correctly in the brain and spinal cord.
Southwood C, He C, Garbern J, Kamholz J, Arroyo E, Gow A. CNS myelin paranodes require Nkx6-2 homeoprotein transcriptional activity for normal structure. J Neurosci. 2004;24(50):11215-11225.
The Gtx homeodomain transcription factor exerts neuroprotection using its homeodomain
2004
This paper shows that Gtx (later renamed Nkx6-2) can protect nerve cells from damage linked to Alzheimer’s disease by boosting a natural growth factor, suggesting a possible new path for developing treatments.
Hashimoto Y, Tsuji O, Kanekura K, Aiso S, Niikura T, Matsuoka M, Nishimoto I. The Gtx homeodomain transcription factor exerts neuroprotection using its homeodomain. J Biol Chem. 2004;279(16):16767-16777.
Complementary roles for Nkx6 and Nkx2 class proteins in the establishment of motoneuron identity in the hindbrain
2003
This paper shows that different Nkx genes work together to guide developing brain cells into becoming the right kinds of motor neurons, ensuring they don’t turn into the wrong cell type and helping them grow and connect properly.
Pattyn A, Vallstedt A, Dias JM, Sander M, Ericson J. Complementary roles for Nkx6 and Nkx2 class proteins in the establishment of motoneuron identity in the hindbrain. Development. 2003;130(17):4149-4159.
Different levels of repressor activity assign redundant and specific roles to Nkx6 genes in motor neuron and interneuron specification
2001
This lab study in mice shows how two related genes, Nkx6.1 and Nkx6.2, act like switches with different strengths to guide the development of different nerve cells in the spinal cord, suggesting they work by turning off genes for other cell types.
Vallstedt A, Muhr J, Pattyn A, Pierani A, Mendelsohn M, Sander M, Jessell TM, Ericson J. Different levels of repressor activity assign redundant and specific roles to Nkx6 genes in motor neuron and interneuron specification. Neuron. 2001;31(5):743-755.
Mice lacking the Nkx6.2 (Gtx) homeodomain transcription factor develop and reproduce normally
2001
This paper describes the creation of mice that are missing the Nkx6.2 gene and finds, surprisingly, that they are healthy and normal, likely because another related gene is doing its job instead.
Cai J, Qi Y, Wu R, Modderman G, Fu H, Liu R, Qiu M. Mice lacking the Nkx6.2 (Gtx) homeodomain transcription factor develop and reproduce normally. Mol Cell Biol. 2001;21(13):4399-4403.
Gtx, an oligodendrocyte-specific homeodomain protein, has repressor activity
2000
This study shows that the oligodendrocyte-specific homeodomain protein Gtx (later named Nkx6-2) functions as a transcriptional repressor through a defined N-terminal domain, but its regulation of myelin gene promoters likely requires interactions with additional transcriptional factors.
Awatramani R, Beesley J, Yang H, Jiang H, Cambi F, Grinspan J, Garbern J, Kamholz J. Gtx, an oligodendrocyte-specific homeodomain protein, has repressor activity. J Neurosci Res. 2000;61(4):376-387.
Evidence that the homeodomain protein Gtx is involved in the regulation of oligodendrocyte myelination
1997
This early study provides evidence that a protein then called Gtx (later named Nkx6-2) is involved in making the protective myelin coating for brain cells, as it appears in the right cells at the right time and binds to myelin-related genes.
Awatramani R, Scherer S, Grinspan J, Collarini E, Skoff R, O’Hagan D, Garbern J, Kamholz J. Evidence that the homeodomain protein Gtx is involved in the regulation of oligodendrocyte myelination. J Neurosci. 1997:17(17):6657-6668.
