FKRP – Muscle-Eye-Brain Disease

Fukutin-related protein (FKRP) is an essential glycosyltransferase required for O-linked glycosylation of α-dystroglycan. Biallelic FKRP mutations cause a spectrum of autosomal recessive dystroglycanopathies, including muscle-eye-brain disease (MEB) characterized by congenital hypotonia, hyperCKaemia, and cerebellar hypoplasia. Clinical validity is classified as Strong based on 17 unrelated probands and concordant segregation and functional studies across multiple cohorts (PMID:23420653).

Genetic Evidence

Inheritance of MEB due to FKRP follows an autosomal recessive pattern. A total of 17 probands have been described: a Moroccan infant with neonatal floppiness and high CK carrying homozygous c.1363G>A (p.Ala455Thr) (PMID:23420653), four non-Japanese patients with phenotypes ranging from Walker-Warburg to MEB-like CMD (PMID:20961758), and six Tunisian patients homozygous for p.Ala455Asp founder variant (PMID:14652796). The variant spectrum includes missense (e.g., p.Ala455Thr), nonsense (e.g., p.Trp432Ter), and frameshift alleles, with recurrent founder mutations in European and North African populations.

Functional Evidence

FKRP localizes to the medial-Golgi apparatus via its N-terminal transmembrane domain. Severe MEB-associated mutations (P448L, A455D) induce ER retention and impaired α-dystroglycan glycosylation in CHO cells (PMID:12471058). Murine knock-in models harboring P448L or Tyr307Asn recapitulate muscle, eye, and brain abnormalities, while FKRP knock-down lines confirm the requirement for FKRP in α-DG functional glycosylation (PMID:19155270, PMID:20675713).

Conflicting Evidence

The Tyr307Asn knock-in mice exhibit minimal phenotype up to 6 months, contrasting with severe human MEB presentations (PMID:19155270), underscoring species-specific differences in FKRP processing and the need for caution when extrapolating murine data.

Conclusion

Strong genetic and moderate functional evidence support FKRP as a definitive gene for muscle-eye-brain disease, guiding molecular diagnosis in neonates with hyperCKaemia and cerebellar hypoplasia. Key Take-home: FKRP sequencing should be included early in the diagnostic work-up for congenital dystroglycanopathies presenting with brain malformations.

References

• Journal of child neurology • 2014 • Elevated serum creatine kinase and small cerebellum prompt diagnosis of congenital muscular dystrophy due to FKRP mutations PMID:23420653
• Neuromuscular disorders • 2011 • Fukutin mutations in non-Japanese patients with congenital muscular dystrophy: less severe mutations predominate in patients with a non-Walker-Warburg phenotype. PMID:20961758
• Neurogenetics • 2004 • New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families. PMID:14652796
• Human molecular genetics • 2002 • Functional requirements for fukutin-related protein in the Golgi apparatus. PMID:12471058
• Brain • 2009 • Reduced expression of fukutin related protein in mice results in a model for fukutin related protein associated muscular dystrophies. PMID:19155270
• Human molecular genetics • 2010 • Fukutin-related protein is essential for mouse muscle, brain and eye development and mutation recapitulates the wide clinical spectrums of dystroglycanopathies. PMID:20675713

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