OMIM Browser
Detalied information of OMIM terms
OMIM No
100720
TI
*100720 CHOLINERGIC RECEPTOR, NICOTINIC, DELTA POLYPEPTIDE; CHRND;;ACETYLCHOLINE RECEPTOR, MUSCLE, DELTA SUBUNIT; ACHRD
OMIM Class
Muscular
TX
For background information on the acetylcholine receptor, see CHRNA1 (100690).
BIOCHEMICAL FEATURES
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 acetylcholine receptor 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.
MAPPING
Heidmann et al. (1986) analyzed restriction fragment length polymorphisms of the 4 subunits of muscle nicotinic acetylcholine receptor 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 acetylcholine receptor 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 no. 1, namely, the cluster of genes for a gamma polypeptide of crystallin (123660-123690). Thus, the gamma and delta subunit genes of acetylcholine receptor 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.
MOLECULAR GENETICS
Engel et al. (1996) identified polymorphisms in the CHRND gene.
- Congenital Myasthenic Syndromes
In a patient with slow-channel congenital myasthenic syndrome (601462), Gomez et al. (2002) identified a heterozygous mutation in the CHRND gene (100720.0001).
In 3 Saudi Arabian patients with fast-channel congenital myasthenic syndrome (608930), Shen et al. (2002) identified a homozygous mutation in the CHRND gene (100720.0002).
- 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).
SA
RF
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. Miyazawa, A.; Fujiyoshi, Y.; Unwin, N.: Structure and gating mechanism of the acetylcholine receptor pore. Nature 423: 949-955, 2003.
9. 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.
10. 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.
11. 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.
CS
AV
| No |
Name |
Disease |
Gene |
Mutation |
| References |
Normal & Mutated sequences |
| 100720.0001 |
MYASTHENIC SYNDROME, CONGENITAL, SLOW-CHANNEL |
|
CHRND |
SER268PHE |
1. Gomez, C. M. et al.
|
|
|
In a single individual with slow-channel congenital myasthenic syndrome (601462) presenting in infancy as progressive weakness, Gomez et al. (2002) identified a heterozygous C-T change 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 acetylcholine receptor (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.
|
| 100720.0002 |
MYASTHENIC SYNDROME, CONGENITAL, FAST-CHANNEL |
|
CHRND |
PRO250GLN |
1. Shen, X.-M. et al.
|
|
|
In 3 Saudi Arabian patients with fast-channel CMS (608930), Shen et al. (2002) identified a homozygous 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 of 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 and current (MEPP and MEPC, respectively) 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.
|
| 100720.0003 |
MYASTHENIC SYNDROME, CONGENITAL, FAST-CHANNEL |
|
CHRND |
GLU59LYS |
1. Brownlow, S. et al.
|
|
|
In a patient with fast-channel CMS (608930) who was born with contractures of both hands, Brownlow et al. (2001) identified compound heterozygosity for 2 mutations in the CHRND gene. One mutation was a 175G-A transition in exon 3, resulting in a glu59-to-lys (E59K) substitution in a conserved extracellular region of the protein, and the second mutation was a 2-bp deletion (756delAG; 100720.0004) in 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.
|
| 100720.0004 |
MYASTHENIC SYNDROME, CONGENITAL, FAST-CHANNEL |
|
CHRND |
2-BP INS, 756AG |
1. Brownlow, S. et al.
|
|
|
See 100720.0003 and Brownlow et al. (2001).
|
| 100720.0005 |
MULTIPLE PTERYGIUM SYNDROME, LETHAL TYPE |
|
CHRND |
TRP57TER |
1. Michalk, A. et al.
|
|
|
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).
|
| 100720.0006 |
MULTIPLE PTERYGIUM SYNDROME, LETHAL TYPE |
|
CHRND |
PHE74LEU |
1. Michalk, A. et al.
|
|
|
In a German family, Michalk et al. (2008) found that lethal multiple pterygium syndrome (253290) in multiple sibs was caused by compound heterozygosity for mutation in the CHRND gene. One allele carried a T-to-C transition in exon 4 (283T-C) that resulted in a phe74-to-leu substitution in the mature protein (F74L; F95L in the precursor). The other allele carried a nonsense mutation (100720.0007).
|
| 100720.0007 |
MULTIPLE PTERYGIUM SYNDROME, LETHAL TYPE |
|
CHRND |
ARG443TER |
1. Michalk, A. et al.
|
|
|
In a German family with multiple sibs affected with multiple pterygium syndrome (253290), Michalk et al. (2008) found compound heterozygosity for mutations 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 (100720.0006).
|
| 100720.0008 |
MYASTHENIC SYNDROME, CONGENITAL, FAST-CHANNEL |
|
CHRND |
LEU42PRO |
1. Shen, X.-M. et al.
|
|
|
In a 20-year-old woman with fast-channel CMS (608930) 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 asn41 with the juxtaposed alpha subunit (CHRNA; 100690) residue tyr127.
|
| 100720.0009 |
MYASTHENIC SYNDROME, CONGENITAL, FAST-CHANNEL |
|
CHRND |
ILE58LYS |
1. Shen, X.-M. et al.
|
|
|
See 100720.0008 and Shen et al. (2008).
|
IMS (Integrated Mutated Sequence)
Create date
2007-10-07 21:22:28
