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.

Intermediate Filament Diseases: Desminopathy

“…10 Although the p.Ala213Val substitution was seen in four control individuals of 199 tested 40 and 2 of 86 analysed for another study, 38 the information generated so far supports the idea that this may be a modifying functional polymorphism. Although p.Ala213Val desmin created a filamentous network in SW13 cells and preserved the existing network in the C2C12 cells, 40 filament assembly experiments showed it aggregated in the viscometer; in the BMGE +H cells, the p.Ala213Val filaments were bundle-like, suggesting that the pathomechanisms of this mutation probably involve subtle but critical interactions with non-IF components in muscle cells. 61 A heterozygous single-nucleotide (adenine) insertion mutation occurring at the third position of codon 241 causes a frameshift leading to serial amino acid replacements: Val242Glu, His243Ser, Glu244Ala and eventually a premature termination signal at codon 245 (numbering according to the updated sequence, GenBank submission # AF167579).…”

“…40,61 However, when the p.Ala360Pro and p.Asn393Ile mutations were cotransfected, this caused devastating effects in each cell line used in the experiment. 40 Indeed, in a family segregating both p.Ala360Pro and p.Asn393Ile mutations, a highly aggressive early onset cardioskeletal myopathy affected only those having both mutations in a compound heterozygous fashion but spared the carriers of either mutation.…”

“…40,61 However, when the p.Ala360Pro and p.Asn393Ile mutations were cotransfected, this caused devastating effects in each cell line used in the experiment. 40 Indeed, in a family segregating both p.Ala360Pro and p.Asn393Ile mutations, a highly aggressive early onset cardioskeletal myopathy affected only those having both mutations in a compound heterozygous fashion but spared the carriers of either mutation. 9 The p.Ala337Pro, p.Leu338Arg, p.Asp399Tyr, p.Glu401Lys and p.Arg406Trp mutations alone make desmin filaments dysfunctional and cause increasingly more severe disease that starts earlier and leads to the development of life-threatening dysphagia, cardiomyopathy, or respiratory weakness.…”

“…9 The p.Ala337Pro, p.Leu338Arg, p.Asp399Tyr, p.Glu401Lys and p.Arg406Trp mutations alone make desmin filaments dysfunctional and cause increasingly more severe disease that starts earlier and leads to the development of life-threatening dysphagia, cardiomyopathy, or respiratory weakness. 40 The severity of illness caused by the mutations located in the C-terminal part of the 2B alphahelical domain can be explained by structural relationships these mutations potentially disrupt. 40 The p.Leu338Arg mutation replaces an apolar amino acid, thus disrupting the highly conserved (abcdefg)n repeat pattern.…”

“…40 The severity of illness caused by the mutations located in the C-terminal part of the 2B alphahelical domain can be explained by structural relationships these mutations potentially disrupt. 40 The p.Leu338Arg mutation replaces an apolar amino acid, thus disrupting the highly conserved (abcdefg)n repeat pattern. The p.Asp399Tyr, p.Glu401Lys and p.Arg406Trp mutations disrupt potentially critical intrahelical and interhelical salt-bridge interactions.…”