Alternative titles; symbols
HGNC Approved Gene Symbol: CHRND
SNOMEDCT: 60192008;
Cytogenetic location: 2q37.1 Genomic coordinates (GRCh38): 2:232,526,160-232,536,664 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q37.1 | ?Myasthenic syndrome, congenital, 3A, slow-channel | 616321 | Autosomal dominant | 3 |
| ?Myasthenic syndrome, congenital, 3C, associated with acetylcholine receptor deficiency | 616323 | Autosomal recessive | 3 | |
| Multiple pterygium syndrome, lethal type | 253290 | Autosomal recessive | 3 | |
| Myasthenic syndrome, congenital, 3B, fast-channel | 616322 | Autosomal recessive | 3 |
The CHRND gene encodes the delta subunit of the nicotinic acetylcholine receptor (AChR), which mediates synaptic transmission at the neuromuscular junction (summary by Muller et al., 2006).
For background information on the AChR, see CHRNA1 (100690).
Michalk et al. (2008) analyzed the expression of acetylcholine receptor (AChR) subunits Chrna1, Chrnb1 (100710), Chrnd, and Chrng (100730), and receptor-associated protein Rapsn (601592), in mouse embryos before (E10.5, E11.5) and during (E12.5, E14.5) muscle development as well as in limb sections with advanced muscle development (E15.5). All studied AChR subunits and Rapsn are expressed in somites as early as E10.5. At E11.5, expression of Chrna1, Chrnb1, Chrnd, Chrng, and Rapsn begins in the developing upper limb and proceeds proximal further into the developing muscle bulks at E12.5. At E14.5, expression corresponds to the muscle anlagen in the trunk, neck, limbs, and diaphragm. Strong expression was also detected in the nuchal musculature, including near the jugular lymphatic sac as well as in the subcutaneous muscle layers.
Crystal Structure
By recording images at liquid-helium temperatures and applying a computational method to correct for distortions, Miyazawa et al. (2003) reported the crystal structure of the AChR of the Torpedo electric ray at a resolution of 4 angstroms. The pore is shaped by an inner ring of 5 alpha helices, which curve radially to create a tapering path for the ions, and an outer ring of 15 alpha helices, which coil around each other and shield the inner ring from the lipids. The gate is a constricting hydrophobic girdle at the middle of a lipid bilayer, formed by weak interactions between neighboring inner helices. When acetylcholine enters the ligand-binding domain, it triggers rotations of the protein chains on opposite sides of the entrance to the pore. These rotations are communicated through the inner helices and open the pore by breaking the girdle apart.
Heidmann et al. (1986) analyzed restriction fragment length polymorphisms of the 4 subunits of muscle nicotinic AChR in 2 mouse species and crosses between the two. They found that the gamma and delta subunit genes cosegregated with each other and with the gene of the fast skeletal muscle isoforms of myosin alkali light chain (160780). The AChR genes cosegregated less tightly with the gene for isocitrate dehydrogenase-1 (147700). The myosin locus and the Idh1 locus are on mouse chromosome 1. IDH1 in man is located on chromosome 2, which carries another locus homologous to one on mouse chromosome 1, namely, the cluster of genes for a gamma polypeptide of crystallin (123660-123690). Thus, the gamma and delta subunit genes of the AChR may be tightly linked to each other and may be situated in man on chromosome 2, possibly on the long arm.
Lobos et al. (1989) found at least 1 RFLP in each of the 4 subunit genes. The delta gene was assigned by in situ hybridization to 2q31-q34. All pairs of RFLPs were analyzed for linkage disequilibrium. Of the 16 pairs of RFLPs from the same gene or from the linked gamma and delta genes, 13 showed evidence of significant disequilibrium (p less than 0.05). By Southern analysis of a panel of somatic cell hybrids and by in situ hybridization, Beeson et al. (1990) assigned the CHRND gene to 2q33-qter. Together with the earlier information, this suggests a location of 2q33-q34. Work of Pasteris et al. (1993) suggested a more distal location; a molecular analysis of a chromosome 2 deletion mapping panel suggested the following order: cen--PAX3--COL4A3--CHRND--tel. PAX3 (606597) is located in band 2q35 and COL4A3 (120070) is located in band 2q36.
Engel et al. (1996) identified polymorphisms in the CHRND gene.
Slow-Channel Congenital Myasthenic Syndrome 3A
In a patient with slow-channel congenital myasthenic syndrome-3A (CMS3A; 616321), Gomez et al. (2002) identified a de novo heterozygous missense mutation in the CHRND gene (S268F; 100720.0001).
Fast-Channel Congenital Myasthenic Syndrome 3B
In 3 Saudi Arabian patients with fast-channel congenital myasthenic syndrome-3B (CMS3B; 616322), Shen et al. (2002) identified a homozygous missense mutation in the CHRND gene (P250Q; 100720.0002).
In a 20-year-old woman with CMS3B, Shen et al. (2008) identified compound heterozygosity for 2 missense mutations in the CHRND gene (L42P, 100720.0008 and I58K, 100720.0009). The L42P substitution resulted in reduced gating efficiency, slower opening of the channel, and decreased probability that the channel would open in response to ACh.
Congenital Myasthenic Syndrome 3C Associated with Acetylcholine Receptor Deficiency
In a German boy with congenital myasthenic syndrome-3C associated with acetylcholine receptor deficiency (CMS3C; 616323), Muller et al. (2006) identified compound heterozygosity for a missense mutation (E318K; 100720.0010) and an intragenic deletion (100720.0011) in the CHRND gene.
Lethal Multiple Pterygium Syndrome
Michalk et al. (2008) identified 2 families, 1 Turkish and 1 German, in which homozygosity or compound heterozygosity for mutations in the CHRND gene (e.g., 100720.0005) resulted in lethal multiple pterygium syndrome (253290).
In a patient with slow-channel congenital myasthenic syndrome-3A (CMS3A; 616321), Gomez et al. (2002) identified a de novo heterozygous C-T transition in exon 8 of the CHRND gene, resulting in a ser268-to-phe (S268F) substitution in the twelfth residue of the delta subunit M2 domain. The mutation was not present in either parent or in 100 normal controls. Functional expression studies showed that the mutation caused delayed closure of AChR ion channels, increasing the propensity for open-channel block, as well as a reduced rate of channel opening. Gomez et al. (2002) suggested that the observations were consistent with steric hindrance on the channel, introduced by the large mutant phenylalanine residue in place of the wildtype serine.
In 3 Saudi Arabian patients with fast-channel congenital myasthenic syndrome-3B (CMS3B; 616322), Shen et al. (2002) identified a homozygous c.749C-A transversion in exon 7 of the CHRND gene, resulting in a pro250-to-gln (P250Q) substitution at the penultimate C-terminal residue of the M1 transmembrane domain. All 3 patients were born to consanguineous parents, and 2 of the patients were first cousins. Functional expression studies showed that the P250Q mutation caused a decreased amplitude of the miniature endplate potential (MEPP) and current (MEPC) to approximately 26 to 35% of normal. The opening burst duration was decreased and disassociation of ACh was increased, resulting in brief channel-opening episodes. In addition, the mutant CHRND protein showed abnormal association with the alpha (CHRNA1; 100690) subunit, resulting in a decreased number of fully assembled AChRs.
In a girl with fast-channel congenital myasthenic syndrome-3B (CMS3B; 616322) who was born with contractures of both hands, Brownlow et al. (2001) identified compound heterozygosity for 2 mutations in the CHRND gene: a 175G-A transition in exon 3, resulting in a glu59-to-lys (E59K) substitution in a conserved extracellular region of the protein, and a 2-bp deletion (756delAG; 100720.0004) in the exon 7/intron 7 boundary, resulting in a null allele. The E59K allele was inherited from the mother and the 2-bp deletion was inherited from the father. Functional expression studies showed reduced adult and fetal AChR expression and a reduced probability of both adult and fetal AChR being in the open state, consistent with a fast-syndrome phenotype.
For discussion of the 756delAG mutation in the CHRND gene that was found in compound heterozygous state in a patient with fast-channel congenital myasthenic syndrome-3B (CMS3B; 616322) by Brownlow et al. (2001), see 100720.0003. (The abstract of the article by Brownlow et al. (2001) described this mutation as 756insAG, whereas the text described it as 756delAG.)
In a consanguineous Turkish family, Michalk et al. (2008) found that lethal multiple pterygium syndrome (253290) in 2 male sibs was caused by homozygosity for a G-to-A transition in exon 3 of the CHRND gene that resulted in a trp57-to-ter amino acid substitution (W57X; W78X in the precursor).
Michalk et al. (2008) found that lethal multiple pterygium syndrome (253290) in multiple sibs in a German family was caused by compound heterozygosity for mutation in the CHRND gene: a T-to-C transition in exon 4 (283T-C), resulting in a phe74-to-leu substitution in the mature protein (F74L; F95L in the precursor), and a nonsense mutation The other allele carried a nonsense mutation (R443X; 100720.0007).
Michalk et al. (2008) found that lethal multiple pterygium syndrome (253290) in multiple sibs in a German family was caused by compound heterozygosity for mutation in the CHRND gene: a 1390C-T transition in exon 12 resulting in an arg443-to-ter (R443X) substitution in the mature protein (R464X in the precursor) on one allele, and on the other a missense mutation (F74L; 100720.0006).
In a 20-year-old woman with fast-channel congenital myasthenic syndrome-3B (CMS3B; 616322) since birth, Shen et al. (2008) identified compound heterozygosity for 2 mutations in the CHRND gene: leu42-to-pro (L42P) and ile58-to-lys (I58K; 100720.0009). In vitro functional expression studies showed that the I58K substitution prevented expression of the delta subunit and was a null mutation. The L42P substitution resulted in reduced gating efficiency, slower opening of the channel, and decreased probability that the channel would open in response to ACh. Further studies showed that the L42P-mutant protein altered the intersubunit linkage of the adjacent delta subunit N41 with the juxtaposed alpha subunit (CHRNA1; 100690) residue Y127.
For discussion of the ile58-to-lys (I58K) mutation in the CHRND gene that was found in compound heterozygous state in a patient with fast-channel congenital myasthenic syndrome-3B (CMS3B; 616322) by Shen et al. (2008), see 100720.0008.
In a German boy with congenital myasthenic syndrome-3C associated with acetylcholine receptor deficiency (CMS3C; 616323), Muller et al. (2006) identified compound heterozygosity for a c.1141G-A transition in exon 10 of the CHRND gene, resulting in a glu381-to-lys (E381K) substitution, and a 2.2-kb deletion (100720.0011) resulting in the loss of half of exon 8 and the entire exon 9. The E381K mutation, which occurred at a highly conserved residue in the cytoplasmic loop, was not found in 200 control alleles. The mutations segregated with the disorder in the family. In vitro functional expression studies in HEK293 cells showed that the E381K mutation resulted in decreased expression of the AChR at the cell surface (about 70% of wildtype). The mutant protein impaired normal clustering of the AChR channel with rapsyn (RAPSN; 601592), which stabilizes the AChR at the cell surface. Muscle biopsy from the patient was not available.
For discussion of 2.2-kb deletion in the CHRND gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-3C associated with acetylcholine receptor deficiency (CMS3C; 616323) by Muller et al. (2006), see 100720.0010.
Beeson, D., Jeremiah, S., West, L. F., Povey, S., Newsom-Davis, J. Assignment of the human nicotinic acetylcholine receptor genes: the alpha and delta subunit genes to chromosome 2 and the beta subunit gene to chromosome 17. Ann. Hum. Genet. 54: 199-208, 1990. [PubMed: 2221824] [Full Text: https://doi.org/10.1111/j.1469-1809.1990.tb00378.x]
Brownlow, S., Webster, R., Croxen, R., Brydson, M., Neville, B., Lin, J.-P., Vincent, A., Newsom-Davis, J., Beeson, D. Acetylcholine receptor delta subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita. J. Clin. Invest. 108: 125-130, 2001. [PubMed: 11435464] [Full Text: https://doi.org/10.1172/JCI12935]
Engel, A. G., Ohno, K., Milone, M., Wang, H.-L., Nakano, S., Bouzat, C., Pruitt, J. N., II, Hutchinson, D. O., Brengman, J. M., Bren, N., Sieb, J. P., Sine, S. M. New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. Hum. Molec. Genet. 5: 1217-1227, 1996. [PubMed: 8872460] [Full Text: https://doi.org/10.1093/hmg/5.9.1217]
Gomez, C. M., Maselli, R. A., Vohra, B. P. S., Navedo, M., Stiles, J. R., Charnet, P., Schott, K., Rojas, L., Keesey, J., Verity, A., Wollmann, R. W., Lasalde-Dominicci, J. Novel delta subunit mutation in slow-channel syndrome causes severe weakness by novel mechanisms. Ann. Neurol. 51: 102-112, 2002. [PubMed: 11782989] [Full Text: https://doi.org/10.1002/ana.10077]
Heidmann, O., Buonanno, A., Geoffroy, B., Robert, B., Guenet, J.-L., Merlie, J. P., Changeux, J.-P. Chromosomal localization of muscle nicotinic acetylcholine receptor genes in the mouse. Science 234: 866-868, 1986. [PubMed: 3022377] [Full Text: https://doi.org/10.1126/science.3022377]
Lobos, E. A., Rudnick, C. H., Watson, M. S., Isenberg, K. E. Linkage disequilibrium study of RFLPs detected at the human muscle nicotinic acetylcholine receptor subunit genes. Am. J. Hum. Genet. 44: 522-533, 1989. [PubMed: 2564730]
Michalk, A., Stricker, S., Becker, J., Rupps, R., Pantzar, T., Miertus, J., Botta, G., Naretto, V. G., Janetzki, C., Yaqoob, N., Ott, C.-E., Seelow, D., and 10 others. Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Am. J. Hum. Genet. 82: 464-476, 2008. [PubMed: 18252226] [Full Text: https://doi.org/10.1016/j.ajhg.2007.11.006]
Miyazawa, A., Fujiyoshi, Y., Unwin, N. Structure and gating mechanism of the acetylcholine receptor pore. Nature 423: 949-955, 2003. [PubMed: 12827192] [Full Text: https://doi.org/10.1038/nature01748]
Muller, J. S., Baumeister, S. K., Schara, U., Cossins, J., Krause, S., von der Hagen, M., Huebner, A., Webster, R., Beeson, D., Lochmuller, H., Abicht, A. CHRND mutation causes a congenital myasthenic syndrome by impairing co-clustering of the acetylcholine receptor with rapsyn. Brain 129: 2784-2793, 2006. [PubMed: 16916845] [Full Text: https://doi.org/10.1093/brain/awl188]
Pasteris, N. G., Trask, B. J., Sheldon, S., Gorski, J. L. Discordant phenotype of two overlapping deletions involving the PAX3 gene in chromosome 2q35. Hum. Molec. Genet. 2: 953-959, 1993. [PubMed: 8103404] [Full Text: https://doi.org/10.1093/hmg/2.7.953]
Shen, X.-M., Fukuda, T., Ohno, K., Sine, S. M., Engel, A. G. Congenital myasthenia-related AChR-delta subunit mutation interferes with intersubunit communication essential for channel gating. J. Clin. Invest. 118: 1867-1876, 2008. [PubMed: 18398509] [Full Text: https://doi.org/10.1172/JCI34527]
Shen, X.-M., Ohno, K., Fukudome, T., Tsujino, A., Brengman, J. M., De Vivo, D. C., Packer, R. J., Engel, A. G. Congenital myasthenic syndrome caused by low-expressor fast-channel AChR-delta subunit mutation. Neurology 59: 1881-1888, 2002. [PubMed: 12499478] [Full Text: https://doi.org/10.1212/01.wnl.0000042422.87384.2f]