Disease relevance of FKRP

• Mutations in the FKRP gene have been identified in seven families with CMD characterized by disease onset in the first weeks of life and a severe phenotype with inability to walk, muscle hypertrophy, marked elevation of serum creatine kinase, and normal brain structure and function [1].
• Congenital muscular dystrophy type 1C and limb girdle muscular dystrophy type 2I are allelic, both being due to mutations in the gene-encoding fukutin-related protein (FKRP) [2].
• CONCLUSIONS: FKRP mutations are a frequent cause of limb-girdle muscular dystrophies [3].
• Limb girdle muscular dystrophy type 2I caused by a novel missense mutation in the FKRP gene presenting as acute virus-associated myositis in infancy [4].
• LGMD2I presenting with a characteristic Duchenne or Becker muscular dystrophy phenotype [5].

Psychiatry related information on FKRP

• New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families [6].

High impact information on FKRP

• Here we identify the gene for a new member of the fukutin protein family (fukutin related protein [FKRP]), mapping to human chromosome 19q13 [1].
• Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan [1].
• We suggest these abnormalities of alpha-dystroglycan are caused by its defective glycosylation and are integral to the pathology seen in MDC1C [1].
• These data provide the first evidence that the ER-retention of mutant FKRP may play a role in the pathogenesis of CMD and potentially explain why the allelic disorder LGMD2I is milder, because the mutated protein is able to reach the Golgi apparatus [7].
• Furthermore, calnexin binds preferentially to the ER-retained mutants suggesting that it may participate in the quality control pathway for FKRP [7].

Biological context of FKRP

• Mutations in four genes (FKT1, POMGnT1, POMT1, FKRP) encoding putative glycosyltransferases have been identified in a subset of patients characterized by a deficient glycosylation of alpha-dystroglycan on muscle biopsy [6].
• Identification of a new microsatellite close to the FKRP gene allowed us to confirm the founder origin of the Tunisian mutation [6].
• We identified a novel missense mutation in exon 4 of the FKRP gene in all the patients studied [8].
• A genome-wide screen followed by fine mapping in this family revealed linkage to a region on chromosome 19 harboring the fukutin-related protein gene (FKRP), with a maximal LOD score of 4.8 for D19S902 [8].
• Motor and sensory nerve conduction velocities (NCVs) and needle electromyography (EMG) results were reviewed in 26 children with different types of congenital muscular dystrophy (CMD), including patients with mutations in the genes LAMA2, FKRP, and COL6A2 [9].

Anatomical context of FKRP

• FKRP was also localized in rough endoplasmic reticulum in skeletal muscle biopsy sample [10].
• FKRP localizes in rough endoplasmic reticulum, while fukutin localizes in the cis-Golgi compartment [10].
• Overall, these data suggest that retention in the endoplasmic reticulum of FKRP is not the main mechanism of disease but that this may instead relate to a disruption of the functional activity of this putative enzyme with its substrate(s) in the Golgi [11].
• Subcellular localization of fukutin and fukutin-related protein in muscle cells [10].
• In differentiated C2C12 myotubes and in transverse sections of normal skeletal and cardiac muscle, endogenous FKRP surrounded the myonuclei [12].

Other interactions of FKRP

• LAMA2 mutations were undetected in 5 patients, in 2 of whom FKRP mutations explained the phenotype [13].
• The entire 1.5-kilobase FKRP coding sequence from patient DNA was analyzed using denaturing high-performance liquid chromatography of overlapping polymerase chain reaction products, followed by direct sequencing of heteroduplexes [3].
• Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome [14].
• The remaining two sons (7 and 10 years old), presented with mild decrease in stamina, had normal neuromuscular examinations and were found to be homozygous for the FKRP mutation in addition to the TRIM32 mutation [15].
• Our findings suggest that, as previously reported for POMT1 and FKRP, mutations in the POMT2 can also be associated with clinical heterogeneity [16].

References