FKRP – Muscular dystrophy-dystroglycanopathy, type A

Autosomal recessive mutations in the fukutin-related protein gene (FKRP) underlie a spectrum of congenital muscular dystrophies characterised by deficient O-linked glycosylation of α-dystroglycan and collectively termed dystroglycanopathies. The most severe form, muscular dystrophy-dystroglycanopathy type A (Walker-Warburg syndrome; MONDO:0000171), manifests in utero or early infancy with cobblestone lissencephaly, eye malformations, hydrocephalus and systemic sequelae. FKRP-related type A dystroglycanopathy is inherited in an autosomal recessive manner, with biallelic pathogenic FKRP variants identified in at least 23 unrelated probands to date, segregating in multiple consanguineous families and supported by concordant functional and animal model data (Strong).

Genetic evidence includes case reports of severe Walker-Warburg phenotypes. A novel frameshift variant, c.558dup (p.Ala187ArgfsTer) in exon 4, was identified in a 16-month-old boy with strabismus, lissencephaly and ocular hypoplasia consistent with type A dystroglycanopathy (PMID:24139536). A Moroccan infant presented with hyperCKaemia, cerebellar hypoplasia and a homozygous missense variant, c.1363G>A (p.Ala455Thr), demonstrating complete loss of α-dystroglycan glycosylation on muscle biopsy (PMID:23420653).

Multi-patient studies further delineate FKRP’s contribution to type A dystroglycanopathy. In a Southern Italian cohort of 153 dystrophinopathy-like patients, 16 (10%) harboured pathogenic FKRP variants, notably the recurrent c.826C>A (p.Leu276Ile) and c.427C>A (p.Arg143Ser), highlighting a population-specific allele frequency (PMID:39408683). An ethnically diverse Walker-Warburg cohort (n=43) yielded FKRP mutations in ~5 individuals, emphasising genetic heterogeneity (PMID:18752264).

The phenotypic spectrum in FKRP-related type A dystroglycanopathy spans neuronal migration defects (cobblestone lissencephaly, HP:0001339), ocular anomalies (microphthalmia, HP:0000568), occipital encephalocele (HP:0002085), ventricular septal defects (HP:0001629) and hydrocephalus (HP:0000238), underscoring the multisystem involvement. Carrier frequency data remain sparse but founder mutations in Tunisian (c.1363G>A) and South African Afrikaner (c.1100T>C; p.Ile367Thr) populations have been documented.

Functional studies establish FKRP’s Golgi localization and critical role in α-dystroglycan glycosylation. FKRP and fukutin co-localise to the medial-Golgi; disease-associated mutations in the DxD motif or Golgi-targeting sequence abrogate Golgi trafficking and alter dystroglycan processing in vitro (PMID:12471058). A P448L knock-in mouse model recapitulates CNS and muscle defects and confirms essential FKRP function in vivo (PMID:20675713).

Therapeutic gene replacement via AAV9-mediated FKRP delivery restores α-dystroglycan glycosylation, ameliorates dystrophic pathology and improves muscle function in murine models bearing the P448L variant, demonstrating proof-of-principle for gene therapy in FKRP-associated dystroglycanopathies (PMID:23817215).

Conflicting data exist for the c.919T>A (p.Tyr307Asn) variant, which causes severe congenital muscular dystrophy in humans with near-absent α-DG but yields no phenotype in homozygous mice, suggesting species-specific differences in FKRP folding or processing (PMID:33051673).

Integration of genetic and experimental evidence supports a Strong ClinGen classification for the FKRP–type A dystroglycanopathy association. Additional mounting high-throughput sequencing data exceed the ClinGen scoring cap. Key Take-home: FKRP variant analysis enables precise diagnosis of type A dystroglycanopathy, informs carrier screening in founder populations and paves the way for emerging gene-based therapies.

References

• Pediatric neurology • 2013 • Eye and brain abnormalities in congenital muscular dystrophies caused by fukutin-related protein gene (FKRP) mutations. PMID:24139536
• Journal of child neurology • 2014 • Elevated serum creatine kinase and small cerebellum prompt diagnosis of congenital muscular dystrophy due to FKRP mutations. PMID:23420653
• Molecular therapy • 2013 • Adeno-associated virus 9 mediated FKRP gene therapy restores functional glycosylation of α-dystroglycan and improves muscle functions PMID:23817215
• Human molecular genetics • 2002 • Functional requirements for fukutin-related protein in the Golgi apparatus. PMID:12471058
• 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
• Human genetics • 2013 • Mouse models of fukutin-related protein mutations show a wide range of disease phenotypes. PMID:23591631
• Neurology. Genetics • 2019 • Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G. PMID:31041397

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