Abstract
Rapsyn, a complex postsynaptic protein of the striated muscle, assembles acetylcholine receptors (AChR) at high density at the motor endplate (EP). Neuromuscular junctions of mice lacking rapsyn show no clusters of AChRs or other structural postsynaptic proteins such as β-dystroglycan and utrophin. Humans with mutations in the rapsyn gene (RAPSN) are affected with a postsynaptic form of congenital myasthenic syndrome (CMS) characterized by impairment of the morphologic development of the postsynaptic region. We have identified four patients from four different families with RAPSN mutations and CMS, confirmed in two cases by microelectrode and electron microscopy studies. The N88K mutation was present in all patients. One patient who was homozygous for N88K was only mildly affected, while the other three patients who were heterozygous for N88K and a second mutation (either L14P, 46insC, or Y269X) were severely affected. Mutations 46insC and Y269X predicts truncation of the protein. L14P predicts a conformational change at the N-terminus that may disrupt membrane association. N88K occurs within the putative leucine zipper motif potentially important for AChR clustering. These findings may explain the severe clinical involvement of compound heterozygous patients.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 204-207 |
| Number of pages | 4 |
| Journal | Journal of Human Genetics |
| Volume | 48 |
| Issue number | 4 |
| DOIs | |
| State | Published - 2003 |
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Keywords
- Acetylcholine receptor clustering
- Congenital myasthenic syndrome
- Endplate
- Postsynaptic
- Rapsyn
ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
Cite this
Identification of pathogenic mutations in the human rapsyn gene. / Dunne, Vanessa; Maselli, Ricardo A.
In: Journal of Human Genetics, Vol. 48, No. 4, 2003, p. 204-207.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Identification of pathogenic mutations in the human rapsyn gene
AU - Dunne, Vanessa
AU - Maselli, Ricardo A
PY - 2003
Y1 - 2003
N2 - Rapsyn, a complex postsynaptic protein of the striated muscle, assembles acetylcholine receptors (AChR) at high density at the motor endplate (EP). Neuromuscular junctions of mice lacking rapsyn show no clusters of AChRs or other structural postsynaptic proteins such as β-dystroglycan and utrophin. Humans with mutations in the rapsyn gene (RAPSN) are affected with a postsynaptic form of congenital myasthenic syndrome (CMS) characterized by impairment of the morphologic development of the postsynaptic region. We have identified four patients from four different families with RAPSN mutations and CMS, confirmed in two cases by microelectrode and electron microscopy studies. The N88K mutation was present in all patients. One patient who was homozygous for N88K was only mildly affected, while the other three patients who were heterozygous for N88K and a second mutation (either L14P, 46insC, or Y269X) were severely affected. Mutations 46insC and Y269X predicts truncation of the protein. L14P predicts a conformational change at the N-terminus that may disrupt membrane association. N88K occurs within the putative leucine zipper motif potentially important for AChR clustering. These findings may explain the severe clinical involvement of compound heterozygous patients.
AB - Rapsyn, a complex postsynaptic protein of the striated muscle, assembles acetylcholine receptors (AChR) at high density at the motor endplate (EP). Neuromuscular junctions of mice lacking rapsyn show no clusters of AChRs or other structural postsynaptic proteins such as β-dystroglycan and utrophin. Humans with mutations in the rapsyn gene (RAPSN) are affected with a postsynaptic form of congenital myasthenic syndrome (CMS) characterized by impairment of the morphologic development of the postsynaptic region. We have identified four patients from four different families with RAPSN mutations and CMS, confirmed in two cases by microelectrode and electron microscopy studies. The N88K mutation was present in all patients. One patient who was homozygous for N88K was only mildly affected, while the other three patients who were heterozygous for N88K and a second mutation (either L14P, 46insC, or Y269X) were severely affected. Mutations 46insC and Y269X predicts truncation of the protein. L14P predicts a conformational change at the N-terminus that may disrupt membrane association. N88K occurs within the putative leucine zipper motif potentially important for AChR clustering. These findings may explain the severe clinical involvement of compound heterozygous patients.
KW - Acetylcholine receptor clustering
KW - Congenital myasthenic syndrome
KW - Endplate
KW - Postsynaptic
KW - Rapsyn
UR - http://www.scopus.com/inward/record.url?scp=0038584915&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0038584915&partnerID=8YFLogxK
U2 - 10.1007/s10038-003-0005-7
DO - 10.1007/s10038-003-0005-7
M3 - Article
VL - 48
SP - 204
EP - 207
JO - Journal of Human Genetics
JF - Journal of Human Genetics
SN - 1434-5161
IS - 4
ER -