PubMed:22453924 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/22453924","sourcedb":"PubMed","sourceid":"22453924","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/22453924","text":"Novel mutation in spectrin-like repeat 1 of dystrophin central domain causes protein misfolding and mild Becker muscular dystrophy.\nMutations in the dystrophin gene without disruption of the reading frame often lead to Becker muscular dystrophy, but a genotype/phenotype correlation is difficult to establish. Amino acid substitutions may disrupt binding capacities of dystrophin and have a major impact on the functionality of this protein. We have identified two brothers (ages 8 and 10 years) with very mild proximal weakness, recurrent abdominal pain, and moderately elevated serum creatine kinase levels. Gene sequencing revealed a novel mutation in exon 11 of the dystrophin gene (c.1280T\u003eC) leading to a L427P amino acid substitution in repeat 1 of the central rod domain. Immunostaining of skeletal muscle showed weak staining of the dystrophin region encoded by exons 7 and 8 corresponding to the end of the actin-binding domain 1 and the N-terminal part of hinge 1. Spectrofluorescence and circular dichroism analysis of the domain repeat 1-2 (R1-2) revealed partial misfolding of the L427P mutated protein as well as a reduced refolding rate after denaturation. Based on computational homology models of the wild-type and mutated R1-2, a molecular dynamics study showed an alteration in the flexibility of the structure, which also strongly affects the conformational space available in the N-terminal region of the fragment. Our results suggest that this missense mutation hinders the dynamic properties of the entire N-terminal region of dystrophin.","tracks":[{"project":"CL-cell","denotations":[{"id":"T1","span":{"begin":768,"end":771},"obj":"Cell"}],"attributes":[{"id":"A1","pred":"cl_id","subj":"T1","obj":"http://purl.obolibrary.org/obo/CL:0000604"},{"subj":"T1","pred":"source","obj":"CL-cell"}]},{"project":"sentences","denotations":[{"id":"TextSentencer_T1","span":{"begin":0,"end":131},"obj":"Sentence"},{"id":"TextSentencer_T2","span":{"begin":132,"end":309},"obj":"Sentence"},{"id":"TextSentencer_T3","span":{"begin":310,"end":441},"obj":"Sentence"},{"id":"TextSentencer_T4","span":{"begin":442,"end":609},"obj":"Sentence"},{"id":"TextSentencer_T5","span":{"begin":610,"end":779},"obj":"Sentence"},{"id":"TextSentencer_T6","span":{"begin":780,"end":975},"obj":"Sentence"},{"id":"TextSentencer_T7","span":{"begin":976,"end":1172},"obj":"Sentence"},{"id":"TextSentencer_T8","span":{"begin":1173,"end":1436},"obj":"Sentence"},{"id":"TextSentencer_T9","span":{"begin":1437,"end":1562},"obj":"Sentence"},{"id":"T1","span":{"begin":0,"end":131},"obj":"Sentence"},{"id":"T2","span":{"begin":132,"end":309},"obj":"Sentence"},{"id":"T3","span":{"begin":310,"end":441},"obj":"Sentence"},{"id":"T4","span":{"begin":442,"end":609},"obj":"Sentence"},{"id":"T5","span":{"begin":610,"end":779},"obj":"Sentence"},{"id":"T6","span":{"begin":780,"end":975},"obj":"Sentence"},{"id":"T7","span":{"begin":976,"end":1172},"obj":"Sentence"},{"id":"T8","span":{"begin":1173,"end":1436},"obj":"Sentence"},{"id":"T9","span":{"begin":1437,"end":1562},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"attributes":[{"subj":"TextSentencer_T1","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T2","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T3","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T4","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T5","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T6","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T7","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T8","pred":"source","obj":"sentences"},{"subj":"TextSentencer_T9","pred":"source","obj":"sentences"},{"subj":"T1","pred":"source","obj":"sentences"},{"subj":"T2","pred":"source","obj":"sentences"},{"subj":"T3","pred":"source","obj":"sentences"},{"subj":"T4","pred":"source","obj":"sentences"},{"subj":"T5","pred":"source","obj":"sentences"},{"subj":"T6","pred":"source","obj":"sentences"},{"subj":"T7","pred":"source","obj":"sentences"},{"subj":"T8","pred":"source","obj":"sentences"},{"subj":"T9","pred":"source","obj":"sentences"}]},{"project":"Glycosmos6-MAT","denotations":[{"id":"T1","span":{"begin":511,"end":519},"obj":"http://purl.obolibrary.org/obo/MAT_0000491"},{"id":"T2","span":{"begin":798,"end":813},"obj":"http://purl.obolibrary.org/obo/MAT_0000302"},{"id":"T3","span":{"begin":807,"end":813},"obj":"http://purl.obolibrary.org/obo/MAT_0000025"}],"attributes":[{"subj":"T1","pred":"source","obj":"Glycosmos6-MAT"},{"subj":"T2","pred":"source","obj":"Glycosmos6-MAT"},{"subj":"T3","pred":"source","obj":"Glycosmos6-MAT"}]},{"project":"DisGeNET","denotations":[{"id":"T0","span":{"begin":44,"end":54},"obj":"gene:1756"},{"id":"T1","span":{"begin":105,"end":130},"obj":"disease:C0917713"},{"id":"T2","span":{"begin":149,"end":159},"obj":"gene:1756"},{"id":"T3","span":{"begin":219,"end":244},"obj":"disease:C0917713"}],"relations":[{"id":"R1","pred":"associated_with","subj":"T0","obj":"T1"},{"id":"R2","pred":"associated_with","subj":"T2","obj":"T3"}],"namespaces":[{"prefix":"gene","uri":"http://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"disease","uri":"http://purl.bioontology.org/ontology/MEDLINEPLUS/"}],"attributes":[{"subj":"T0","pred":"source","obj":"DisGeNET"},{"subj":"T1","pred":"source","obj":"DisGeNET"},{"subj":"T2","pred":"source","obj":"DisGeNET"},{"subj":"T3","pred":"source","obj":"DisGeNET"}]},{"project":"PubmedHPO","denotations":[{"id":"T1","span":{"begin":226,"end":244},"obj":"HP_0003560"},{"id":"T2","span":{"begin":540,"end":554},"obj":"HP_0002027"},{"id":"T3","span":{"begin":550,"end":554},"obj":"HP_0012531"},{"id":"T4","span":{"begin":571,"end":601},"obj":"HP_0003236"}],"attributes":[{"subj":"T1","pred":"source","obj":"PubmedHPO"},{"subj":"T2","pred":"source","obj":"PubmedHPO"},{"subj":"T3","pred":"source","obj":"PubmedHPO"},{"subj":"T4","pred":"source","obj":"PubmedHPO"}]},{"project":"Allie","denotations":[{"id":"SS1_22453924_6_0","span":{"begin":1042,"end":1052},"obj":"expanded"},{"id":"SS2_22453924_6_0","span":{"begin":1054,"end":1058},"obj":"abbr"}],"relations":[{"id":"AE1_22453924_6_0","pred":"abbreviatedTo","subj":"SS1_22453924_6_0","obj":"SS2_22453924_6_0"}],"attributes":[{"subj":"SS1_22453924_6_0","pred":"source","obj":"Allie"},{"subj":"SS2_22453924_6_0","pred":"source","obj":"Allie"}]},{"project":"DisGeNET5_gene_disease","denotations":[{"id":"22453924-0#44#54#gene1756","span":{"begin":44,"end":54},"obj":"gene1756"},{"id":"22453924-0#105#130#diseaseC0917713","span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