Alternative titles; symbols
HGNC Approved Gene Symbol: RAPSN
Cytogenetic location: 11p11.2 Genomic coordinates (GRCh38): 11:47,437,764-47,449,136 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p11.2 | Fetal akinesia deformation sequence 2 | 618388 | Autosomal recessive | 3 |
| Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency | 616326 | Autosomal recessive | 3 |
The RAPSN gene encodes a postsynaptic protein that connects and stabilizes acetylcholine receptors (AChR) at the neuromuscular junction (Apel et al., 1995).
Frail et al. (1988) identified a mammalian homolog of the 43-kD acetylcholine receptor-associated protein found in the postsynaptic membranes of the electric organ in Torpedo. The cDNA was isolated from the BC3H1 mouse muscle cell line. Because this is a receptor-associated protein of synapses it was designated rapsyn. The predicted 412-amino acid mouse protein is 70% identical to the Torpedo protein and contains a conserved cAMP-dependent protein kinase phosphorylation site. Northern blot analysis detected a 2.0-kb transcript in muscle of newborn and 4-week-old mice, and Southern blots suggested that the gene is present in single copy in mice. Buckel et al. (1996) isolated a cDNA for rapsyn (RAPSN) from human muscle and showed that the predicted protein (also 412 residues) is 96% identical to the mouse protein.
Michalk et al. (2008) analyzed the expression of AChR subunits Chrna1 (100690), Chrnb1 (100710), Chrnd (100720), Chrng (100730), and of Rapsn 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.
Gaudon et al. (2010) noted that the RAPSN gene contains 8 exons.
Buckel et al. (1996) used a combination of somatic cell hybrid and radiation hybrid DNA panels to map the RAPSN gene to chromosome 11p11.2-p11.1.
In the dystrophin-glycoprotein complex (DGC) in skeletal muscle, dystroglycan (DAG1; 128239) binds to agrin (AGRN; 103320), a component of the synaptic basal lamina. Apel et al. (1995) found that dystroglycan colocalized with AChR-rapsyn clusters on the cell surface in vitro. Furthermore, dystroglycan colocalized with rapsyn even in the absence of AChR, indicating that rapsyn can cluster dystroglycan and AChR independently. The authors concluded that rapsyn is a molecular link connecting the AChR to the cytoskeleton-anchored DGC at the neuromuscular junction, thereby stabilizing AChR clustering.
Ramarao et al. (2001) analyzed the structural and functional domains of rapsyn by using targeted mutations to disrupt different areas of the protein. The coiled-coil domain at residues 298 to 331 was necessary for AChR clustering at the postsynaptic membrane, and self-association of rapsyn required at least 2 tetratricopeptide repeats (TPRs).
Rodova et al. (2004) found that Ctnnd2 (604275) formed a complex with Kaiso (ZBTB33; 300329), and that both proteins localized to nuclei of C2C12 mouse myocytes and to the postsynaptic domain of the mouse neuromuscular junction. Chromatin immunoprecipitation analysis of C2C12 cells showed that endogenous Kaiso coprecipitated with the Rapsyn promoter. Minimal promoter assays demonstrated that mouse Kaiso and Ctnnd2 activated the mouse and human RAPSYN promoter, and a human cell line lacking Ctnnd2 expression showed no Kaiso-mediated RAPSYN activation. Site-specific mutation of the RAPSYN promoter to produce the -38A-G (601592.0006) mutation that causes postsynaptic congenital myasthenic syndrome (CMS; 608931) resulted in reduced Kaiso-mediated activation of the RAPSYN promoter. Rodova et al. (2004) concluded that KAISO, CTNND2, and myogenic transcription factors regulate synapse-specific transcription of RAPSYN.
Congenital Myasthenic Syndrome 11 Associated With Acetylcholine Receptor Deficiency
Congenital myasthenic syndromes (CMSs) stem from genetic defects in endplate-specific presynaptic, synaptic, and postsynaptic proteins. The postsynaptic congenital myasthenic syndromes stem from a deficiency or kinetic abnormality of the acetylcholine receptor (AChR). In 4 patients with congenital myasthenic syndrome-11 (CMS11; 616326) and AChR deficiency but with no mutations in AChR units, Ohno et al. (2002) identified 3 recessive mutations in the RAPSN gene (601592.0001-601592.0003). Endplate studies in each case showed decreased staining for rapsyn and AChR, as well as impaired postsynaptic morphologic development. Expression studies in HEK cells indicated that none of the mutations hindered rapsyn self-association, but that all 3 diminished coclustering of AChR with rapsyn. Rapsyn self-association precedes recruitment of AChR to rapsyn clusters. Seven tetratricopeptide repeats of rapsyn subserve self-association.
Muller et al. (2006) identified 3 different mutations in the RAPSN gene (601592.0007-601592.0009) in 2 unrelated patients with CMS and AChR deficiency. The authors noted that neither patient carried the common N88K (601592.0001) mutation that had been reported in most patients of western European origin.
By in vitro cellular functional expression assays, Cossins et al. (2006) demonstrated that pathogenic missense mutations in the RAPSN gene disrupted RAPSN function through different intracellular mechanisms. The R91L mutation inhibited RAPSN self-clustering; K373del, A25V, and L361R resulted in variably decreased RAPSN protein levels suggesting reduced stability; A25V, N88K, and L361R showed decreased or absent association with AChR; A25V abrogated AChR clustering; and N88K and L361R formed unstable agrin-induced AChR clusters. The pathogenic effects of N88K and L361R were more subtle compared to the other mutations. All 15 patients studied carried the N88K mutation on at least 1 allele. Although there was no clear relationship between the location of the mutations and disease severity, patients who were compound heterozygous for N88K and another mutation tended to have a more severe phenotype, suggesting that the second mutant allele may largely determine the phenotype.
Gaudon et al. (2010) found that 3 (15%) of 20 unrelated patients with CMS due to RAPSN mutations were compound heterozygous for the common N88K mutation and an intragenic multiexonic deletion in the RAPSN gene. The 3 different deletions, which encompassed the first exons, middle exons, and last exons, respectively, were detected by SNP analysis and gene dosage studies. Two of the deletions occurred between repeated sequences within the RAPSN gene. Gaudon et al. (2010) suggested that RAPSN may be particularly prone to genomic recombination, as it has numerous repeated sequences,
Fetal Akinesia Deformation Sequence 2
Because defects in the embryonal acetylcholine receptor (CHRNG; 100730) can cause either lethal or nonlethal (Escobar type) multiple pterygium syndrome (MPS) (253290 or 265000, respectively), Vogt et al. (2008) analyzed 15 patients with lethal MPS or fetal akinesia without a CHRNG mutation for mutations in CHRNA1 (100690), CHRNB1 (100710), CHRND (100720), and RAPSN. No CHRNA1, CHRNB1, or CHRND mutations were detected, but a homozygous RAPSN frameshift mutation, 1177-1178delAA (601592.0012), was identified in a family with 3 children affected with lethal fetal akinesia deformation sequence (FADS2; 618388). Functional studies were consistent with the hypothesis that whereas incomplete loss of rapsyn function may cause congenital myasthenia, more severe loss of function can result in a lethal fetal akinesia phenotype.
In a Pakistani family, Michalk et al. (2008) found that compound heterozygosity for missense mutations in the RAPSN gene (601592.0013-601592.0014) caused fetal akinesia syndrome with congenital contractures in 2 sibs. Respiratory distress resulted in the death of 1 sib at age 10 months.
Dunne and Maselli (2003) reported 4 patients with congenital myasthenic syndrome associated with AChR deficiency caused by mutation in the RAPSN gene. One patient was homozygous for the N88K mutation and had the mildest symptoms; moreover, his 33-year-old asymptomatic mother had the same genotype. In contrast, 3 other patients who were compound heterozygous for N88K and another mutation had a severe phenotype. Dunne and Maselli (2003) noted that N88K interferes with AChR clustering, whereas the other mutations either truncated the protein or altered membrane attachment. In compound heterozygotes, the combination of disruptive mechanisms leads to a more severe phenotype.
Dunne and Maselli (2004) stated that all previously reported patients with postsynaptic CMS carried the N88K mutation. They used 7 intragenic SNPs spanning 8 kb to characterize the haplotype associated with N88K. In 3 affected N88K homozygous individuals, they identified a common haplotype present in all heterozygous carriers of N88K. Of note, in 2 asymptomatic N88K homozygous individuals, a second haplotype was present and differed at 3 SNP sites downstream from the N88K mutation. The finding of a common haplotype associated with N88K supported a founder effect. The discordant haplotype in homozygous individuals suggested that recombination events may have occurred within the RAPSN gene and that this may have implications in the phenotypic expression of the disease.
By haplotype analysis of 21 CMS patients of European and Indian origin with the N88K mutation, Muller et al. (2004) identified a core founder haplotype of 10 SNPs encompassing a region of 0.36 Mb flanking the mutation and concluded that N88K derived from a single founder event in an ancient Indo-European population.
Gautam et al. (1995) generated transgenic mice with targeted disruption of the Rapsn gene. Homozygous mutants were born in expected numbers and were similar in appearance to normal littermates, but died within hours after birth. The mutant mice had difficulty breathing and were unable to support themselves on all fours or to lift their heads. Analysis of the neuromuscular junction showed that there were no detectable AChR clusters along the length of muscle fibers, indicating that Rapsn is essential for AChR aggregation at the developing neuromuscular junction.
Lin et al. (2001) noted that isolated gene knockout studies in transgenic mice indicated the involvement of agrin, muscle-specific kinase (MuSK; 601296), and rapsn in clustering AChR at the neuromuscular junction. Lin et al. (2001) analyzed early stages of postsynaptic differentiation in muscles of mutant mice lacking agrin, MuSK, rapsyn, and/or motor nerves. The authors found that the defect in MuSK mutants is due to an absence of initiation of postsynaptic differentiation, whereas the impairment in agrin mutants is caused by loss of agrin-dependent maintenance of the postsynaptic apparatus. On the basis of these and previous studies, Lin et al. (2001) proposed the existence of 3 early overlapping steps in the formation of the postsynaptic apparatus at the neuromuscular junction. First, a muscle-intrinsic, nerve/agrin-independent and MuSK-dependent mechanism initiates formation of postsynaptic specialization in an endplate band. Second, nerve-derived agrin acts through MuSK to promote apposition of nerve terminals to these nerve-independent acetylcholine receptor clusters and/or to induce new postsynaptic sites. Agrin is also required for the growth and maintenance of most, if not all, synaptic sites. Third, motor axons, or Schwann cells that accompany them, provide an agrin-independent signal that destabilizes or disperses postsynaptic apparatus that have not been stabilized by agrin.
In 2 patients with congenital myasthenic syndrome-11 (CMS11; 616326) associated with AChR deficiency, Ohno et al. (2002) identified a homozygous asn88-to-lys (N88K) mutation in the RAPSN gene. The N88K mutation was identified in the compound heterozygous state with leu14-to-pro (L14P; 601592.0002) in one patient and with 553ins5 (601592.0003) in another. The N88K substitution results from a 264C-A transversion in exon 2 of the RAPSN gene (Muller et al., 2004).
Dunne and Maselli (2003) identified the N88K mutation in each of 4 patients from 4 different families with CMS and AChR deficiency. One patient was homozygous for N88K and was only mildly affected, whereas the other 3 patients were heterozygous for N88K and a second mutation (L14P; 601592.0002), (46insC; 601592.0004), or (Y269X; 601592.0005) and were severely affected. The authors noted that the N88K mutation occurs within the putative leucine zipper motif, which is important for clustering of the acetylcholine receptor.
Among 120 CMS patients from 110 unrelated families, Muller et al. (2003) identified the N88K mutation in 12 patients (10%) from 10 families. Seven patients were homozygous for the mutation and 5 patients were compound heterozygous. Genotype analysis of the region of chromosome 11 close to the RAPSN gene suggested that the N88K allele derived from a common European ancestor.
Burke et al. (2003) reported 16 patients with CMS caused by the N88K mutation: 7 were homozygous and 9 were compound heterozygous.
By haplotype analysis of 21 CMS patients of European and Indian origin with the N88K mutation, Muller et al. (2004) identified a core founder haplotype of 10 SNPs encompassing a region of 0.36 Mb flanking the mutation and concluded that N88K derived from a single founder event in an ancient Indo-European population.
Skeie et al. (2006) reported a boy with an unusually mild CMS phenotype who was homozygous for the N88K mutation. Until age 5 years, he had repeated episodes of weakness with respiratory insufficiency and swallowing difficulties associated with febrile illnesses. By age 19, he participated in normal physical activity, experiencing only occasional muscle cramps and ptosis. He was always symptom-free between attacks and had normal serologic tests, normal acetylcholine receptor levels, no decrement on repetitive muscle stimulation, and no response to acetylcholinesterase inhibitors. The findings expanded the phenotype associated with the N88K mutation.
For discussion of the leu14-to-pro (L14P) mutation in the RAPSN gene that was found in compound heterozygous state in patients with myasthenic syndrome-11 (CMS11; 616326) associated with AChR deficiency by Ohno et al. (2002), see 601592.0001.
Dunne and Maselli (2003) noted that the L14P substitution predicts a conformational change at the N terminus that may disrupt membrane association.
For discussion of the 5-bp insertion in the RAPSN gene (553ins5) that was found in compound heterozygous state in patients with congenital myasthenic syndrome-11 (CMS11; 616326) associated with AChR deficiency by Ohno et al. (2002), see 601592.0001.
In a patient with congenital myasthenic syndrome-11 (CMS11; 616326) associated with AChR deficiency, Dunne and Maselli (2003) identified compound heterozygosity for the N88K mutation (601592.0001) and a 46insC mutation in exon 1 of the RAPSN gene, resulting in premature termination of the protein.
In a patient with congenital myasthenic syndrome-11 (CMS11; 616326) associated with AChR deficiency, Dunne and Maselli (2003) identified compound heterozygosity for the N88K mutation (601592.0001) and an 807C-A transition in exon 5 of the RAPSN gene, resulting in a tyr269-to-ter (Y269X) mutation causing premature termination of the protein.
In 6 patients with congenital myasthenic syndrome-11 (CMS11; 616326) associated with AChR deficiency and facial dysmorphism, Ohno et al. (2003) identified a homozygous -38A-G transition in the promoter region of the RAPSN gene. All patients were of either Iraqi or Iranian origin and were first reported by Goldhammer et al. (1990). Haplotype analysis showed a founder effect for the mutation. Functional expression studies suggested that the -38G-A mutation impaired transcription, leading to reduced RAPSN expression, and endplate AChR deficiency.
Rodova et al. (2004) showed that site-specific mutation of the RAPSYN promoter to produce the -38A-G mutation resulted in reduced muscle-specific activation of the promoter by mouse Kaiso (ZBTB33; 300329) and Ctnnd2 (604275).
In a 9-year-old girl with congenital myasthenic syndrome-11 (CMS11; 616326) associated with AChR deficiency, Muller et al. (2006) identified compound heterozygosity for a leu283-to-pro (L283P) substitution in exon 5 and a C-to-A transversion in intron 1 (IVS1-15C-A; 601592.0008) of the RAPSN gene. The patient was born of a German father and a Czech mother. Clinical features included congenital contractures, apnea in the newborn period, seizures, hypotonia, and good response to AChE inhibitor treatment. Transfection studies indicated that the splice site mutation resulted in abnormal splicing and premature termination of the protein in exon 2. The L283P substitution occurs in the linker between the seventh tetratricopeptide repeat and the coiled-coil region of the protein. Functional expression studies showed that the L283P mutant protein resulted in decreased coclustering of RAPSN with AChR.
For discussion of the splice site mutation in the RAPSN gene (IVS1-15C-A) that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-11 (CMS11; 616326) and AChR deficiency by Muller et al. (2006), see 601592.0007.
In a 12-year-old Serbian patient with congenital myasthenic syndrome-11 (CMS11; 616326) and AChR deficiency, Muller et al. (2006) identified a homozygous mutation in exon 2 of the RAPSN gene, resulting in an arg164-to-cys (R164C) substitution in the highly conserved fifth tetratricopeptide repeat of the protein. Functional expression studies showed that the R164C mutant protein resulted in decreased coclustering of RAPSN with AChR.
In a 16-month-old girl with congenital myasthenic syndrome-11 (CMS11; 616326) and AChR deficiency, Maselli et al. (2007) identified compound heterozygosity for 2 mutations in the RAPSN gene: a 133G-A transition in exon 1, resulting in a val45-to-met (V45M) substitution, and a 284G-A transition in exon 2, resulting in a glu162-to-lys (E162K) substitution (601592.0011). The patient required mechanical ventilation in the newborn period. Clinical features included normal cognition, bilateral ptosis, normal ocular movements, and mild facial and proximal limb weakness. Functional expression studies showed that the V45M mutant protein resulted in diminished coclustering of RAPSN with AChR. Transfection experiments indicated that the E162K mutation resulted in decreased coclustering of RAPSN with AChR.
For discussion of the glu162-to-lys (E162K) mutation in the RAPSN gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-11 (CMS11; 616326) and AChR deficiency by Maselli et al. (2007), see 601592.0010.
In 3 fetuses with fetal akinesia deformation sequence (FADS2; 618388) from a consanguineous family, Vogt et al. (2008) found a homozygous deletion in exon 8 of the RAPSN gene, 1177-1178delAA. Both parents were heterozygotes for the mutation. The family presented when fetal akinesia sequence was detected at 19 weeks' gestation in twin male fetuses. On ultrasound examination, both fetuses had micrognathia and fixed position of the hands, elbows, and feet. There were no respiratory movements. The pregnancy was terminated at 23 weeks' gestation. Postmortem examination revealed monochorionic, monoamniotic twins with no evidence of growth retardation. A subsequent female singleton fetus was similarly affected. Fetal akinesia sequence was detected on ultrasound at 19 weeks of gestation, and the pregnancy was terminated at 23 weeks. Again, postmortem examination showed dysmorphologic features including short broad neck but no pterygia. The 1177-1178delAA mutation predicts a frameshift after residue 392 of rapsyn resulting in 82 C-terminal missense amino acids. Functional studies demonstrated severe loss of function, with failure to cluster the AChR. This mutation had been found by Burke et al. (2003) in compound heterozygosity with the N88K allele (601592.0001) in patients with congenital myasthenic syndrome (CMS11; 616326).
In a Pakistani family, Michalk et al. (2008) observed compound heterozygosity for 2 missense RAPSN mutations as the basis of fetal akinesia sequence (FADS2; 618388) with severe contractures and respiratory and feeding abnormalities at birth. One allele carried a 416T-C transition in exon 2 resulting in a phe139-to-ser substitution (F139S); the other carried a 566C-T transition in exon 3 resulting in an ala189-to-val substitution (A189V). Both residues are conserved across species, indicating functional relevance.
For discussion of the ala189-to-val (A189V) mutation in the RAPSN gene that was found in compound heterozygous state in patients with fetal akinesia sequence (FADS2; 618388) by Michalk et al. (2008), see 601592.0013.
In a boy with congenital myasthenic syndrome-11 (CMS11; 616326) associated with AChR deficiency, Das et al. (2014) identified compound heterozygous mutations in the RAPSN gene: a 2-bp duplication (c.1083_1084dupCT), resulting in a frameshift and premature termination (Tyr362SerfsTer10), and the common N88K mutation (601592.0001). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. The patient had severe muscle weakness and responded dramatically to anticholinesterase treatment. Functional studies of the variants were not performed.
Apel, E. D., Roberds, S. L., Campbell, K. P., Merlie, J. P. Rapsyn may function as a link between the acetylcholine receptor and the agrin-binding dystrophin-associated glycoprotein complex. Neuron 15: 115-126, 1995. [PubMed: 7619516] [Full Text: https://doi.org/10.1016/0896-6273(95)90069-1]
Buckel, A., Beeson, D., James, M., Vincent, A. Cloning of cDNA encoding human rapsyn and mapping of the RAPSN gene locus to chromosome 11p11.2-p11.1. Genomics 35: 613-616, 1996. [PubMed: 8812503] [Full Text: https://doi.org/10.1006/geno.1996.0409]
Burke, G., Cossins, J., Maxwell, S., Owens, G., Vincent, A., Robb, S., Nicolle, M., Hilton-Jones, D., Newsom-Davis, J., Palace, J., Beeson, D. Rapsyn mutations in hereditary myasthenia: distinct early- and late-onset phenotypes. Neurology 61: 826-828, 2003. [PubMed: 14504330] [Full Text: https://doi.org/10.1212/01.wnl.0000085865.55513.ae]
Cossins, J., Burke, G., Maxwell, S., Spearman, H., Man, S., Kuks, J., Vincent, A., Palace, J., Fuhrer, C., Beeson, D. Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations. Brain 129: 2773-2783, 2006. [PubMed: 16945936] [Full Text: https://doi.org/10.1093/brain/awl219]
Das, A. S., Agamanolis, D. P., Cohen, B. H. Use of next-generation sequencing as a diagnostic tool for congenital myasthenic syndrome. Pediat. Neurol. 51: 717-720, 2014. [PubMed: 25194721] [Full Text: https://doi.org/10.1016/j.pediatrneurol.2014.07.032]
Dunne, V., Maselli, R. A. Identification of pathogenic mutations in the human rapsyn gene. J. Hum. Genet. 48: 204-207, 2003. [PubMed: 12730725] [Full Text: https://doi.org/10.1007/s10038-003-0005-7]
Dunne, V., Maselli, R. A. Common founder effect of rapsyn N88K studied using intragenic markers. J. Hum. Genet. 49: 366-369, 2004. [PubMed: 15252722] [Full Text: https://doi.org/10.1007/s10038-004-0159-y]
Frail, D., McLaughlin, L., Mudd, J., Merlie, J. Identification of the mouse muscle 43,000-Dalton acetylcholine receptor-associated protein (RAPsyn) by cDNA cloning. J. Biol. Chem. 263: 15602-15607, 1988. [PubMed: 3170600]
Gaudon, K., Penisson-Besnier, I., Chabrol, B., Bouhour, F., Demay, L., Ben Ammar, A., Bauche, S., Vial, C., Nicolas, G., Eymard, B., Hantai, D., Richard, P. Multiexon deletions account for 15% of congenital myasthenic syndromes with RAPSN mutations after negative DNA sequencing. J. Med. Genet. 47: 795-796, 2010. [PubMed: 20930056] [Full Text: https://doi.org/10.1136/jmg.2010.081034]
Gautam, M., Noakes, P. G., Mudd, J., Nichol, M., Chu, G. C., Sanes, J. R., Merlie, J. P. Failure of postsynaptic specialization to develop at neuromuscular junctions of rapsyn-deficient mice. Nature 377: 232-236, 1995. [PubMed: 7675108] [Full Text: https://doi.org/10.1038/377232a0]
Goldhammer, Y., Blatt, I., Sadeh, M., Goodman, R. M. Congenital myasthenia associated with facial malformations in Iraqi and Iranian Jews: a new genetic syndrome. Brain 113: 1291-1306, 1990. [PubMed: 2245297] [Full Text: https://doi.org/10.1093/brain/113.5.1291]
Lin, W., Burgess, R. W., Dominguez, B., Pfaff, S. L., Sanes, J. R., Lee, K.-F. Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature 410: 1057-1064, 2001. [PubMed: 11323662] [Full Text: https://doi.org/10.1038/35074025]
Maselli, R. A., Dris, H., Schnier, J., Cockrell, J. L., Wollmann, R. L. Congenital myasthenic syndrome caused by two non-N88K rapsyn mutations. (Letter) Clin. Genet. 72: 63-65, 2007. [PubMed: 17594401] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00824.x]
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]
Muller, J. S., Abicht, A., Burke, G., Cossins, J., Richard, P., Baumeister, S. K., Stucka, R., Eymard, B., Hantai, D., Beeson, D., Lochmuller, H. The congenital myasthenic syndrome mutation RAPSN N88K derives from an ancient Indo-European founder. (Letter) J. Med. Genet. 41: e104, 2004. Note: Electronic Article. [PubMed: 15286164] [Full Text: https://doi.org/10.1136/jmg.2004.021139]
Muller, J. S., Baumeister, S. K., Rasic, V. M., Krause, S., Todorovic, S., Kugler, K., Muller-Felber, W., Abicht, A., Lochmuller, H. Impaired receptor clustering in congenital myasthenic syndrome with novel RAPSN mutations. Neurology 67: 1159-1164, 2006. [PubMed: 16931511] [Full Text: https://doi.org/10.1212/01.wnl.0000233837.79459.40]
Muller, J. S., Mildner, G., Muller-Felber, W., Schara, U., Krampfl, K., Petersen, B., Petrova, S., Stucka, R., Mortier, W., Bufler, J., Kurlemann, G., Huebner, A., Merlini, L., Lochmuller, H., Abicht, A. Rapsyn N88K is a frequent cause of congenital myasthenic syndromes in European patients. Neurology 60: 1805-1810, 2003. [PubMed: 12796535] [Full Text: https://doi.org/10.1212/01.wnl.0000072262.14931.80]
Ohno, K., Engel, A. G., Shen, X.-M., Selcen, D., Brengman, J., Harper, C. M., Tsujino, A., Milone, M. Rapsyn mutations in humans cause endplate acetylcholine-receptor deficiency and myasthenic syndrome. Am. J. Hum. Genet. 70: 875-885, 2002. [PubMed: 11791205] [Full Text: https://doi.org/10.1086/339465]
Ohno, K., Sadeh, M., Blatt, I., Brengman, J. M., Engel, A. G. E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome. Hum. Molec. Genet. 12: 739-748, 2003. [PubMed: 12651869] [Full Text: https://doi.org/10.1093/hmg/ddg089]
Ramarao, M. K., Bianchetta, M. J., Lanken, J., Cohen, J. B. Role of rapsyn tetratricopeptide repeat and coiled-coil domains in self-association and nicotinic acetylcholine receptor clustering. J. Biol. Chem. 276: 7475-7483, 2001. [PubMed: 11087759] [Full Text: https://doi.org/10.1074/jbc.M009888200]
Rodova, M., Kelly, K. F., VanSaun, M., Daniel, J. M., Werle, M. J. Regulation of the rapsyn promoter by Kaiso and delta-catenin. Molec. Cell. Biol. 24: 7188-7196, 2004. [PubMed: 15282317] [Full Text: https://doi.org/10.1128/MCB.24.16.7188-7196.2004]
Skeie, G. O., Aurlien, H., Muller, J. S., Lochmuller, H., Norgard, G., Bindoff, L. A. Unusual features in a boy with the rapsyn N88K mutation. Neurology 67: 2262-2263, 2006. [PubMed: 17190963] [Full Text: https://doi.org/10.1212/01.wnl.0000249184.09369.c2]
Vogt, J., Harrison, B. J., Spearman, H., Cossins, J., Vermeer, S., ten Cate, L. N., Morgan, N. V., Beeson, D., Maher, E. R. Mutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients. Am. J. Hum. Genet. 82: 222-227, 2008. [PubMed: 18179903] [Full Text: https://doi.org/10.1016/j.ajhg.2007.09.016]