Disease relevance of DYSF

• BACKGROUND: Mutations in the dysferlin (DYSF) gene cause 3 different phenotypes of muscular dystrophies: Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal anterior compartment myopathy [1].
• Mutations in the human dysferlin gene ( DYSF) cause autosomal recessive muscular dystrophies characterized by degeneration and weakness of proximal and/or distal muscles: limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM) [2].
• Clinical and genetic analysis of Korean patients with Miyoshi myopathy: identification of three novel mutations in the DYSF gene [3].
• Although MM patients and their mutations in the DYSF gene have been found from all over the world, there is only one report of genetically confirmed case of MM in Korea. Recently, we encountered three unrelated Korean patients with MM and two of them have previously been considered as having a type of inflammatory myopathy [3].
• Limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM), a distal muscular dystrophy, are both caused by mutations in the recently cloned gene dysferlin, gene symbol DYSF [4].

Psychiatry related information on DYSF

• Dysferlin is a plasma membrane protein and is expressed early in human development [5].

High impact information on DYSF

• Identical mutations in the dysferlin gene can produce more than one myopathy phenotype (MM, limb girdle dystrophy, distal myopathy with anterior tibial onset) [6].
• Using a positional cloning approach, we have identified the gene for a form of limb-girdle muscular dystrophy that we previously mapped to chromosome 2p13 (LGMD2B) [7].
• The proposed name 'dysferlin' combines the role of the gene in producing muscular dystrophy with its C. elegans homology [7].
• Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy [6].
• Dysferlin and the plasma membrane repair in muscular dystrophy [8].

Chemical compound and disease context of DYSF

• Lariat branch point mutation in the dysferlin gene with mild limb-girdle muscular dystrophy [9].
• Results included the identification of novel tandem repeats in the human X-linked retinitis pigmentosa type-2 gene product, repeated segments in cystinosin, associated with a defect in cystine transport, and 'nested' homologous domains in dysferlin, whose gene is mutated in limb girdle muscular dystrophy [10].
• In young patients with sporadic proximal weakness, very high creatine kinase levels, necrotic fibers and inflammation in the muscle biopsy, a diagnosis of dysferlin myopathy should be considered [11].
• Novel sequence variants in dysferlin-deficient muscular dystrophy leading to mRNA decay and possible C2-domain misfolding [12].

Biological context of DYSF

• Gene analysis revealed a frameshift mutation in the exon 50 (delG5966) of the DYSF gene [13].
• CONCLUSIONS: The new R1905X DYSF founder mutation produced the 3 possible dysferlinopathy phenotypes without intrafamilial heterogeneity [1].
• RESULTS: All the patients presented the R1905X mutation in the DYSF gene in homozygosity, and the haplotype analysis at the DYSF locus revealed that it was a novel and founder mutation [1].
• Refined mapping of the Welander distal myopathy region on chromosome 2p13 positions the new candidate region telomeric of the DYSF locus [14].
• Molecular analysis of LGMD-2B and MM patients: identification of novel DYSF mutations and possible founder effect in the Italian population [15].

Anatomical context of DYSF

• The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle [16].
• This is the first description of a possible dysferlin interacting protein; it suggests the hypothesis that one function of dysferlin may be to interact with caveolin-3 to subserve signaling functions of caveolae [16].
• The immunoreactivity of affixin was reduced in sarcolemma of MM and LGMD2B muscles, although the total amount of the affixin protein was normal [17].
• Analysis of human fetal tissue showed that dysferlin was expressed at the earliest stages of development examined, at Carnegie stage 15 or 16 (embryonic age 5-6 weeks) [5].
• In vitro, immunohistochemistry, semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and real-time PCR showed that both dysferlin mRNA and protein expression were higher in multinucleated myotubes than in the myoblast stage (p < 0.05) [18].

Associations of DYSF with chemical compounds

• Direct DNA sequencing of whole exons of DYSF gene revealed one homozygous missense mutation (G1165C) on exon 12, which let to an amino acid substitution from the glutamic acid to glutamine at the 389 of the peptide sequence in this patient [19].
• RESULTS: All patients were characterized by early adult onset, preferential atrophy, and weakness of calf muscles, marked elevation of serum creatine kinase levels, and absence of dysferlin staining [20].
• Although its function is still unknown, it is inferred from the presence of C2 domains and a transmembrane domain in its sequence that dysferlin may be expressed or located not only at the sarcolemma but also in other membranous organelles to interact with Ca(2+) [21].
• Changes in dysferlin, proteins from dystrophin glycoprotein complex, costameres, and cytoskeleton in human soleus and vastus lateralis muscles after a long-term bedrest with or without exercise [22].
• Sequence and predicted structural comparisons have highlighted the high degree of similarity of dysferlin and FER1L3, which have sequences corresponding to six C2 domains and which share more than 60% amino acid sequence identity [23].

Physical interactions of DYSF

• We report that dysferlin co-immunoprecipitates with caveolin-3 from biopsied normal human skeletal muscles [16].
• Mutation finding in patients with dysferlin deficiency and role of the dysferlin interacting proteins annexin A1 and A2 in muscular dystrophies [24].

Other interactions of DYSF

• The immunoprecipitation data are consistent with the parallel observation that dysferlin immunostaining is not normal in LGMD1C muscles [16].
• Immunostaining of TAs was also seen with antibodies against heat shock protein and dysferlin, but not with antibodies to lamin A, dystrophin, adhalin, beta, gamma, delta sarcoglycans, and merosin [25].
• Definite heterozygotes from 4 families (3 LGMD2B and 1 LGMD2E) underwent quantitative immunoblot analysis of mutant protein in their muscle [26].
• Myoferlin is a novel protein of unknown function with high homology to dysferlin, the gene mutations of which cause limb girdle muscular dystrophy type 2B and Miyoshi myopathy [27].
• MRE compensates the cytoskeletal changes induced by LTBR in SOL, except for gamma-sarcoglycan (+70%) and dysferlin (+108%) [22].

Analytical, diagnostic and therapeutic context of DYSF

• A primary screening of DYSF using SSCP or dHPLC of PCR products of each of 55 exons of the gene was followed by sequencing whenever a sequence variation was detected [28].
• On western blots of muscle, LGMD2B and MM patients show a similar abundance in dysferlin staining of 15 and 11%, respectively [4].
• Flow cytometry and immunofluorescence also showed reduced levels of myogenin in dysferlin-deficient cultures [29].
• Electron microscopy showed that control cultured cells at 10 days were fusiform, whereas dysferlin-deficient cells were star-shaped and large [29].
• In RIPA fractions, dysferlin was seen as 230-272 kDa bands in normal and AD brains [30].

References