title: Variable pathogenic potentials of mutations located in the desmin alpha-helical domain.
abstract: Mutations in the desmin gene have been recognized as a cause of desminopathy, a familial or sporadic disorder characterized by skeletal muscle weakness, often associated with cardiomyopathy or respiratory insufficiency. Distinctive histopathologic features include aberrant intracytoplasmic accumulation of desmin (DES). We present here comparative phenotypic, molecular, and functional characteristics of four novel and three previously reported, but not fully characterized, desmin mutations localized in desmin alpha-helical domain. The results indicate that the c.638C>T (p.A213V), c.1178A>T (p.N393I), and to some extent the c.1078G>C (p.A360P) mutations exhibit pathogenic potentials only if combined with other mutations in desmin or other genes and should therefore be considered conditionally pathogenic. The c.1009G>C (p.A337P), c.1013T>G (p.L338R), c.1195G>T (p.D399Y), and c.1201G>A (p.E401K) mutations make desmin filaments dysfunctional and are capable of causing disease. The pathogenic potentials of desmin mutations correlate with the type and location of the disease-associated mutations in the relatively large and structurally and functionally complex desmin molecule. Mutations within the highly conserved alpha-helical structures are especially damaging since the integrity of the alpha-helix is critical for desmin filament assembly and stability.
authors.affiliation: EA300, Université Paris 7 Denis Diderot, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Goudeau
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrigues-Lima
authors.forename: Dirk
authors.initials: D
authors.lastname: Fischer
authors.forename: Monique
authors.initials: M
authors.lastname: Casteras-Simon
authors.forename: Nyamkhishig
authors.initials: N
authors.lastname: Sambuughin
authors.forename: Marianne
authors.initials: M
authors.lastname: de Visser
authors.forename: Pascal
authors.initials: P
authors.lastname: Laforet
authors.forename: Xavier
authors.initials: X
authors.lastname: Ferrer
authors.forename: Françoise
authors.initials: F
authors.lastname: Chapon
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sjöberg
authors.forename: Anna
authors.initials: A
authors.lastname: Kostareva
authors.forename: Thomas
authors.initials: T
authors.lastname: Sejersen
authors.forename: Marinos C
authors.initials: MC
authors.lastname: Dalakas
authors.forename: Lev G
authors.initials: LG
authors.lastname: Goldfarb
authors.forename: Patrick
authors.initials: P
authors.lastname: Vicart
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D003893:Desmin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010641:Phenotype; D017433:Protein Structure, Secondary; D016415:Sequence Alignment
chemical_list: D003893:Desmin