Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: CHN1
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38): 2:174,798,809-175,005,381 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.1 | Duane retraction syndrome 2 | 604356 | Autosomal dominant | 3 |
Hall et al. (1990) isolated a novel human brain cDNA sequence encoding n-chimerin, a 34-kD protein. They found that the N-terminal half shared almost 50% identity with sequences in the regulatory domain of protein kinase C (176960); the C-terminal half had 42% identity with the C-terminal region of BCR, the product of the breakpoint cluster region gene involved in the Philadelphia chromosome translocation (151410).
Also known as alpha-1-chimerin, n-chimerin is a brain GTPase-activating protein (GAP) for the RAS-related p21 (RAC). Hall et al. (1993) found another form of chimerin, termed alpha-2-chimerin, and showed that it is the product of an alternately spliced transcript of the human n-chimerin gene. The mRNAs corresponding to the 2 forms of chimerin were expressed differently.
By Western blot analysis of mouse hippocampal lysates, Buttery et al. (2006) found alpha-1-chimerin levels slowly increased during the first 2 weeks of postnatal development. Highest expression was in neurons of the hippocampus and cortex, as well as Purkinje cells in the cerebellum. Cultured hippocampal neurons also showed a developmental increase in alpha-1-chimerin, and expression was highly sensitive to synaptic activity inhibitors. Stimulation of phospholipase C-beta (PLCB; see 607120)-coupled receptors recruited alpha-1-chimerin to the plasma membrane of cultured hippocampal neurons, and increased alpha-1-chimerin activity resulted in the pruning of dendritic spines and branches, which required both the diacylglycerol-binding and Rac GAP activity of alpha-1-chimerin. Suppression of alpha-1-chimerin resulted in increased process growth from the dendritic shaft and from spine heads. Buttery et al. (2006) concluded that alpha-1-chimerin is an activity-dependent Rho GTPase regulator that is activated by PLCB-coupled cell surface receptors.
Ephrins and their receptors play critical roles in axon guidance and growth cone collapse by regulating small Rho GTPases. Shi et al. (2007) showed that alpha-2-chimerin was required for Epha4 (602188)-dependent growth cone collapse. Prominent expression of alpha-2-chimerin was detected in rat brain and cortical neurons and was enriched in postsynaptic density fractions. The SH2 domain of alpha-2-chimerin interacted specifically with Epha4 in rat brain in a kinase-dependent manner. Ephrin-A1 (EFNA1; 191164)-stimulated activation of Epha4 resulted in phosphorylation of alpha-2-chimerin and increased alpha-2-chimerin GAP activity toward Rac1 (602048), which was required for Epha4-dependent growth cone collapse.
Hall et al. (1993) mapped the human n-chimerin gene to chromosome 2q31-q32.1 by Southern analysis of a hybrid cell DNA panel and by fluorescence in situ hybridization.
Miyake et al. (2008) found 7 missense mutations in the CHN1 gene (118423.0001-118423.0007) resulting in Duane retraction syndrome-2 (DURS2; 604356). These gain-of-function mutations increased alpha-2-chimerin RacGAP activity in vitro. Several mutations appeared to enhance alpha-2-chimerin translocation to the cell membrane or enhanced its ability to self-associate. Expression of mutant alpha-2-chimerin constructs in chick embryos resulted in failure of oculomotor axons to innervate their target extraocular muscles. Miyake et al. (2008) concluded that alpha-2-chimerin has a critical developmental function in ocular motor axon pathfinding. Five of the 7 mutations resulted in nonconservative amino acid substitutions. All were predicted to alter amino acids that are conserved in 8 different species. All 7 nucleotide substitutions cosegregated with the affected haplotypes, and none were present in online SNP databases or on 788 control chromosomes.
In affected members of 2 families segregating DURS2 as a dominant trait, Chan et al. (2011) identified heterozygous missense mutations in the CHN1 gene (118423.0008-118423.0009). Both mutations altered residues that participate in intramolecular interactions that stabilize the inactive, closed conformation of alpha-2-chimerin and are thus predicted to result in its hyperactivation.
In a large Mexican American family with Duane retraction syndrome-2 (DURS; 604356) initially described by Engle et al. (2007), Miyake et al. (2008) identified an A-to-T transversion at nucleotide 60 in exon 3 of the CHN1 gene, resulting in a leucine-to-phenylalanine substitution at codon 20 (L20F). This mutation segregated with the affected family members and was not identified in 788 control subjects.
In a Mexican family segregating Duane retraction syndrome-2 (DURS; 604356), Miyake et al. (2008) identified a T-to-G transversion at nucleotide 378 in exon 6 of the CHN1 gene, resulting in an isoleucine-to-methionine substitution at codon 126 (I126M). This mutation segregated with the disorder in the family and was not identified in 788 control chromosomes.
In a US Caucasian family with Duane retraction syndrome-2 (DURS; 604356) initially described by Engle et al. (2007), Miyake et al. (2008) identified a T-to-C transition at nucleotide 427 in exon 6 of the CHN1 gene, resulting in a tyrosine-to-histidine substitution at codon 143 (Y143H). This mutation segregated with affected members in the family and was not identified in 788 controls.
In a 4-generation family with Duane retraction syndrome-2 (DURS; 604356) initially described by Evans et al. (2000), Miyake et al. (2008) identified a C-to-T transition at nucleotide 668 in exon 8 of the CHN1 gene, resulting in an alanine-to-valine substitution at codon 223 (A223V). This mutation segregated with affected members in the pedigree and was not identified in 788 control chromosomes.
In an Italian Caucasian segregating Duane retraction syndrome-2 (DURS; 604356), Miyake et al. (2008) identified a G-to-A transition at nucleotide 682 in exon 8 of the CHN1 gene, resulting in a glycine-to-serine substitution at codon 228 (G228S). This mutation was not identified in 788 control chromosomes, and segregated with the phenotype in the family.
In a large Mexican family with Duane retraction syndrome-2 (DURS2; 604356) previously reported by Appukuttan et al. (1999), Miyake et al. (2008) identified a C-to-A transversion at nucleotide 755 in exon 9 of the CHN1 gene, resulting in a proline-to-glutamine substitution at codon 252 (P252Q). This mutation segregated with the phenotype in the family, and was not identified in 788 control chromosomes.
In a U.S. Caucasian family segregating Duane retraction syndrome-2 (DURS2; 604356), Miyake et al. (2008) identified a G-to-A transition at nucleotide 937 in exon 10 of the CHN1 gene, resulting in a glutamic acid-to-lysine substitution at codon 313 (E313K). This mutation segregated with affected family members of the pedigree and was not identified in 788 control chromosomes.
In affected members of a family segregating Duane retraction syndrome-2 (DURS2; 604356), Chan et al. (2011) identified heterozygosity for a 422C-T transition in the CHN1 gene, resulting in a pro141-to-leu (P141L) substitution. Pro141 participates in intramolecular interactions that stabilize the inactive, closed conformation of alpha-2-chimerin and is thus predicted to result in its hyperactivation.
In affected members of a family segregating Duane retraction syndrome-2 (DURS2; 604356), Chan et al. (2011) identified heterozygosity for a 752C-T transition in the CHN1 gene, resulting in a pro252-to-ser (P252S) substitution. Pro252 participates in intramolecular interactions that stabilize the inactive, closed conformation of alpha-2-chimerin and is thus predicted to result in its hyperactivation. Chan et al. (2011) noted that another mutation at this codon (P252G; 118423.0006) had been found to cause DURS2.
Appukuttan, B., Gillanders, E., Juo, S.-H., Freas-Lutz, D., Ott, S., Sood, R., Van Auken, A., Bailey-Wilson, J., Wang, X., Patel, R. J., Robbins, C. M., Chung, M., Annett, G., Weinberg, K., Borchert, M. S., Trent, J. M., Brownstein, M. J., Stout, J. T. Localization of a gene for Duane retraction syndrome to chromosome 2q31. Am. J. Hum. Genet. 65: 1639-1646, 1999. [PubMed: 10577917] [Full Text: https://doi.org/10.1086/302656]
Buttery, P., Beg, A. A., Chih, B., Broder, A., Mason, C. A., Scheiffele, P. The diacylglycerol-binding protein alpha-1-chimaerin regulates dendritic morphology. Proc. Nat. Acad. Sci. 103: 1924-1929, 2006. [PubMed: 16446429] [Full Text: https://doi.org/10.1073/pnas.0510655103]
Chan, W.-M., Miyake, N., Zhu-Tam, L., Andrews, C., Engle, E. C. Two novel CHN1 mutations in 2 families with Duane retraction syndrome. Arch. Ophthal. 129: 649-652, 2011. [PubMed: 21555619] [Full Text: https://doi.org/10.1001/archophthalmol.2011.84]
Engle, E. C., Andrews, C., Law, K., Demer, J. L. Two pedigrees segregating Duane's retraction syndrome as a dominant trait map to the DURS2 genetic locus. Invest. Ophthal. Vis. Sci. 48: 189-193, 2007. [PubMed: 17197532] [Full Text: https://doi.org/10.1167/iovs.06-0631]
Evans, J. C., Frayling, T. M., Ellard, S., Gutowski, N. J. Confirmation of linkage of Duane's syndrome and refinement of the disease locus to an 8.8-cM interval on chromosome 2q31. Hum. Genet. 106: 636-638, 2000. [PubMed: 10942112] [Full Text: https://doi.org/10.1007/s004390000311]
Hall, C., Monfries, C., Smith, P., Lim, H. H., Kozma, R., Ahmed, S., Vanniasingham, V., Leung, T., Lim, L. Novel human brain cDNA encoding a 34,000 M(r) protein n-chimaerin, related to both the regulatory domain of protein kinase C and BCR, the product of the breakpoint cluster region gene. J. Molec. Biol. 211: 11-16, 1990. [PubMed: 2299665] [Full Text: https://doi.org/10.1016/0022-2836(90)90006-8]
Hall, C., Sin, W. C., Teo, M., Michael, G. J., Smith, P., Dong, J. M., Lim, H. H., Manser, E., Spurr, N. K., Jones, T. A., Lim, L. Alpha-2-chimerin, an SH2-containing GTPase-activating protein for the ras-related protein p21-rac derived by alternate splicing of the human n-chimerin gene, is selectively expressed in brain regions and testes. Molec. Cell. Biol. 13: 4986-4998, 1993. [PubMed: 8336731] [Full Text: https://doi.org/10.1128/mcb.13.8.4986-4998.1993]
Miyake, N., Chilton, J., Psatha, M., Cheng, L., Andrews, C., Chan, W.-M., Law, K., Crosier, M., Lindsay, S., Cheung, M., Allen, J., Gutowski, N. J., and 15 others. Human CHN1 mutations hyperactivate alpha-2-chimaerin and cause Duane's retraction syndrome. Science 321: 839-843, 2008. [PubMed: 18653847] [Full Text: https://doi.org/10.1126/science.1156121]
Shi, L., Fu, W.-Y., Hung, K.-W., Porchetta, C., Hall, C., Fu, A. K. Y., Ip, N. Y. Alpha-2-chimaerin interacts with EphA4 and regulates EphA4-dependent growth cone collapse. Proc. Nat. Acad. Sci. 104: 16347-16352, 2007. [PubMed: 17911252] [Full Text: https://doi.org/10.1073/pnas.0706626104]