title: New intronic splicing mutation in the LMNA gene causing progressive cardiac conduction defects and variable myopathy.
abstract: BACKGROUND
  Most of mutations in the LMNA gene are unique and have been found in only a few unrelated families. The clinical interpretation of new genetic variants, especially beyond the coding area and canonical splice sites, is proving to be difficult and requires advanced investigation.
  
  
  METHODS
  This study included patients with progressive cardiac conduction defects with neuromuscular involvement. The clinical evaluation included medical history and 24-h Holter monitoring. The genetic evaluation included mutation screening in the LMNA gene by the Sanger sequence. Sanger sequencing was followed by RT-PCR of the target fragment of cDNA. In silico modeling was performed with CCBulder and Modeller software.
  
  
  RESULTS
  The diagnosis of limb-girdle muscular dystrophy type 1B (LGMD1B) was established. The new intronic variant c.513+45T>G was found in the LMNA gene in the proband and affected daughter. The insertion of 45bp was confirmed in the proband's cDNA. The structural and possible functional effects of the aberrant protein were predicted.
  
  
  CONCLUSIONS
  Variant c.513+45T>G in the LMNA gene likely translates into the longer lamin A/C proteins with additional 15 amino acids. This variant is thought to be pathogenic. Intronic variants in the LMNA gene located beside canonic splice sites may be responsible for some genotype-negative cases with clinical phenotype of laminopathies.
authors.affiliation: Petrovsky Russian Research Center of Surgery, Abricosovsky pereulok, 119991 Moscow, Russia. Electronic address: julia.rogozhina@gmail.com.
authors.forename: Y
authors.initials: Y
authors.lastname: Rogozhina
authors.affiliation: Petrovsky Russian Research Center of Surgery, Abricosovsky pereulok, 119991 Moscow, Russia.
authors.forename: S
authors.initials: S
authors.lastname: Mironovich
authors.affiliation: Petrovsky Russian Research Center of Surgery, Abricosovsky pereulok, 119991 Moscow, Russia.
authors.forename: A
authors.initials: A
authors.lastname: Shestak
authors.affiliation: Research Centre of Medical Genetics, Moskvorechie street, 115478 Moscow, Russia; Pirogov Russian National Research Medical University, Ostrovityanova str. 1, Moscow 117997, Russia.
authors.forename: T
authors.initials: T
authors.lastname: Adyan
authors.affiliation: Research Centre of Medical Genetics, Moskvorechie street, 115478 Moscow, Russia.
authors.forename: A
authors.initials: A
authors.lastname: Polyakov
authors.affiliation: Petrovsky Russian Research Center of Surgery, Abricosovsky pereulok, 119991 Moscow, Russia.
authors.forename: D
authors.initials: D
authors.lastname: Podolyak
authors.affiliation: Novosibirsk State University, Pirogova str. 2, Novosibirsk, Russia.
authors.forename: A
authors.initials: A
authors.lastname: Bakulina
authors.affiliation: Petrovsky Russian Research Center of Surgery, Abricosovsky pereulok, 119991 Moscow, Russia.
authors.forename: S
authors.initials: S
authors.lastname: Dzemeshkevich
authors.affiliation: Petrovsky Russian Research Center of Surgery, Abricosovsky pereulok, 119991 Moscow, Russia; Pirogov Russian National Research Medical University, Ostrovityanova str. 1, Moscow 117997, Russia.
authors.forename: E
authors.initials: E
authors.lastname: Zaklyazminskaya
mesh_terms: D000328:Adult; D053840:Brugada Syndrome / Q000209:etiology / Q000235:genetics*; D000075224:Cardiac Conduction System Disease; D003198:Computer Simulation; D003402:Creatine Kinase / Q000097:blood; D005260:Female; D006801:Humans; D007438:Introns; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D008297:Male; D049288:Muscular Dystrophies, Limb-Girdle / Q000209:etiology / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D022821:RNA Splice Sites; D012326:RNA Splicing
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D022821:RNA Splice Sites; D003402:Creatine Kinase
keywords: Deep intronic mutation; Defect splice site mutation; Lamin; Lamin A/C-dependent limb-girdle muscular dystrophy type 1B