FKTN – Muscle-eye-brain Disease

Fukutin (FKTN) is a putative glycosyltransferase encoded by HGNC:3622 and is causally associated with muscle-eye-brain disease (MONDO:0018939), an autosomal recessive dystroglycanopathy characterized by congenital muscular dystrophy, cobblestone lissencephaly (HP:0007260), and ocular malformations. The phenotype overlaps Fukuyama congenital muscular dystrophy and Walker–Warburg syndrome, reflecting the shared mechanism of α-dystroglycan hypoglycosylation.

Autosomal recessive inheritance of FKTN variants was established initially in Japanese cohorts, with haplotype analysis in 56 families demonstrating segregation of founder (A-F) and non-founder alleles correlating with typical and severe phenotypes (PMID:10817652). Sequence-based confirmation in non-Japanese populations includes a Turkish patient homozygous for c.454dup (p.Ser152fs) (PMID:12601708) and additional non-Japanese probands compound heterozygous for missense and truncating mutations (PMID:20961758). These data encompass more than 60 unrelated families with consistent autosomal recessive segregation, supporting a strong gene–disease relationship.

The clinical spectrum includes severe developmental delay, eye anomalies, and variable motor milestones. Type II lissencephaly and cobblestone cortical malformation are hallmarks, while ocular defects range from microphthalmia to cataracts. Carrier frequency for the founder insertion is high in Japan; however, non-founder and hypomorphic alleles contribute to a broad phenotype.

Functional studies reveal that fukutin localizes to the medial–Golgi via its N-terminus and transmembrane domains, where it is required for post-translational glycosylation of α-dystroglycan. Overexpression of FKRP alters dystroglycan processing, and FKTN variants fail to localize to the Golgi, resulting in hypoglycosylation (PMID:12471058; PMID:22275357). Direct nano-LC–MS³ mapping demonstrates that FKTN is essential for ribitol phosphate transfer onto α-DG at Thr317/Thr319, a modification prevented by FKTN knockout (PMID:27601598).

Therapeutic strategies have emerged from splicing studies targeting branchpoints and deep-intronic variants. Antisense oligonucleotide correction of the SINE-VNTR-Alu insertion and pseudoexon inclusion (c.647+2084G>T; c.648-1243G>T) restores normal FKTN mRNA and protein production in patient cells, offering proof of concept for exon-skipping approaches (PMID:37547287; PMID:36426838).

Integration of robust genetic evidence from >60 families, consistent autosomal recessive segregation, and concordant functional data confirms FKTN as a definitive disease gene for muscle-eye-brain disease, guiding molecular diagnosis worldwide. Key take-home: FKTN mutation analysis is critical for clinical diagnosis, and emerging RNA-based therapies hold promise to correct glycosylation defects.

References

• American journal of medical genetics • 2000 • Haplotype-phenotype correlation in Fukuyama congenital muscular dystrophy. PMID:10817652
• Annals of neurology • 2003 • A new mutation of the fukutin gene in a non-Japanese patient. PMID:12601708
• Neuromuscular disorders : NMD • 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
• Human molecular genetics • 2002 • Functional requirements for fukutin-related protein in the Golgi apparatus. PMID:12471058
• The Journal of biological chemistry • 2012 • Mislocalization of fukutin protein by disease-causing missense mutations can be rescued with treatments directed at folding amelioration. PMID:22275357
• Molecular & cellular proteomics : MCP • 2016 • Direct Mapping of Additional Modifications on Phosphorylated O-glycans of α-Dystroglycan by Mass Spectrometry Analysis in Conjunction with Knocking Out of Causative Genes for Dystroglycanopathy PMID:27601598
• Molecular therapy. Nucleic acids • 2023 • Branchpoints as potential targets of exon-skipping therapies for genetic disorders. PMID:37547287
• Human molecular genetics • 2023 • Antisense oligonucleotide induced pseudoexon skipping and restoration of functional protein for Fukuyama muscular dystrophy caused by a deep-intronic variant. PMID:36426838

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