KDM6B
Lysine demethylase 6B is a protein that in humans is encoded by the KDM6B (JMJD3) gene.[5]
Regulation during differentiation
KDM6B was found to be expressional increased during cardiac and endothelial differentiation of murine embryonic stem cells.[6]
Small molecule inhibition
A small molecule inhibitor (GSK-J1) has been developed to inhibit the jumonji domain of KDM6 histone demethylase family to modulate proinflammatory response in macrophages.[7]
Role in pathology
Mutations of the KDM6B gene may cause neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, which was first described in 2019 by Stolerman et al.[8]
Standard laboratory exome sequencing can be used to identify the KDM6B gene variant.
Clinical picture
A 2019 study[8] on symptoms from KDM6B variations reported:
- Delays in speech and motor development
- Dysmorphic facial features including coarse features, a prominent forehead, broad mouth, large and prominent ears, a round face, prognathism, and epicanthal fold
- Musculoskeletal features including somewhat widened and thickened hands and fingers, joint hypermobility, clinodactyly of the fifth fingers, and toe syndactyly
- Neuromuscular hypotonia
- Intellectual disability
- Autism spectrum disorder
A further 2023 international study [9] reported on the following clinical features among individuals with (likely) pathogenic KDM6B variants:
| Feature Name | p value | Total % |
|---|---|---|
| Males | 0.50 | 73% |
| Increased birth weight [>2 SD] | 0.33 | 17% |
| Increased weight [>2 SD] | 0.59 | 14% |
| Tall stature [>2 SD] | 1.0 | 8% |
| Macrocephaly [>2 SD] | 1.0 | 26% |
| At least one feature of overgrowth syndrome | 1.0 | 30% |
| Language/speech delay | 0.15 | 94% |
| Motor delay | 1.0 | 89% |
| Intellectual disability | 0.14 | 63% |
| Autism spectrum (ASD) | 0.51 | 61% |
| Behavior problems, non-ASD | 0.70 | 60% |
| Psychotic disorders [≥12 years old] | 1.0 | 20% |
| Seizures | 0.58 | 13% |
| Sleep disturbances | 0.09 | 32% |
| Movement disorder/gait disturbances/hypertonia/ataxia | 0.67 | 24% |
| Hypotonia | 1.0 | 57% |
| Neonatal feeding difficulties or gastroesophageal reflux | 1.0 | 51% |
| Constipation | 1.0 | 18% |
| Congenital heart disease | 0.58 | 13% |
| Cleft lip/palate/uvula | 0.03b | 4% |
| Genitourinary system abnormalities | 1.0 | 10% |
| Joint hypermobility | 1.0 | 42% |
| Scoliosis/kyphosis/lordosis | 0.58 | 13% |
| Syndactyly | 0.15 | 9% |
| Short fingers or toes | 1.0 | 9% |
| Broad fingers/fingertips/hands/toes/feet | 1.0 | 20% |
| Myopia/amblyopia | 0.08 | 33% |
| Strabismus | 0.58 | 13% |
| Hearing loss | 1.0 | 2% |
| Recurrent ear infections | 1.0 | 12% |
Epidemiology
For patients reporting intellectual disability and/or developmental delay, approximately 0.12% have de novo alterations in the KDM6B gene.
Related conditions
Overlapping phenotypic features for patients between KDM6A associated with Kabuki syndrome and KDM6B variations include prominent ears, abnormal dentition, congenital heart disease, feeding difficulties, cryptorchidism, joint hyper-mobility, developmental delay, hypotonia, and behavioral difficulties.
Ongoing research
According to a study published in 2022, pathologic mutations of KDM6B were found in five patients with cerebral folate deficiency.[10]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000132510 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000018476 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: Lysine demethylase 6B". Retrieved 2016-04-09.
- ^ Boeckel JN, Derlet A, Glaser SF, Luczak A, Lucas T, Heumüller AW, et al. (July 2016). "JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial Cells". Arteriosclerosis, Thrombosis, and Vascular Biology. 36 (7): 1425–1433. doi:10.1161/ATVBAHA.116.307695. PMID 27199445.
- ^ Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K, Joberty G, et al. (August 2012). "A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response". Nature. 488 (7411): 404–408. Bibcode:2012Natur.488..404K. doi:10.1038/nature11262. PMC 4691848. PMID 22842901.
- ^ a b Stolerman ES, Francisco E, Stallworth JL, Jones JR, Monaghan KG, Keller-Ramey J, et al. (July 2019). "Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features". American Journal of Medical Genetics. Part A. 179 (7): 1276–1286. doi:10.1002/ajmg.a.61173. PMID 31124279. S2CID 163167304.
- ^ Rots D, Jakub TE, Keung C, Jackson A, Banka S, Pfundt R, et al. (June 2023). "The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder". American Journal of Human Genetics. 110 (6): 963–978. doi:10.1016/j.ajhg.2023.04.008. PMC 10257005. PMID 37196654.
- ^ Han X, Cao X, Cabrera RM, Pimienta Ramirez PA, Zhang C, Ramaekers VT, et al. (December 2022). "KDM6B Variants May Contribute to the Pathophysiology of Human Cerebral Folate Deficiency". Biology. 12 (1): 74. doi:10.3390/biology12010074. PMC 9855468. PMID 36671766.
Further reading
- Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, et al. (October 2007). "UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development". Nature. 449 (7163): 731–734. Bibcode:2007Natur.449..731A. doi:10.1038/nature06145. PMID 17713478. S2CID 4413812.
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