MFSD8 – Neuronal ceroid lipofuscinosis (CLN7)

Late-infantile neuronal ceroid lipofuscinosis type 7 (CLN7) is an autosomal recessive neurodegenerative lysosomal storage disorder caused by biallelic variants in MFSD8. A genome-wide linkage and sequencing study in a consanguineous Egyptian family identified a novel homozygous missense variant, c.362A>G (p.Tyr121Cys), in exon 5 of MFSD8 that segregated with disease in three affected siblings presenting with seizures and psychomotor decline (PMID:18850119). Expanded case series and cohorts have reported over 100 affected individuals from more than 20 unrelated families harboring diverse MFSD8 variants—including missense, frameshift, splice-site, and small in-frame deletions—confirming autosomal recessive inheritance and consistent clinical features of seizures (HP:0001250), neurodegeneration (HP:0002180), ataxia (HP:0001251), and progressive visual loss (HP:0000529) ([PMID:18850119]; [PMID:25270050]).

Segregation in multiple consanguineous and non-consanguineous pedigrees, combined with functional studies, underpins a definitive gene–disease relationship. Cellular and animal models demonstrate that loss-of-function MFSD8 variants impair lysosomal targeting, disrupt autophagy, and lead to accumulation of autofluorescent storage material, recapitulating human pathology (PMID:17564970). A rabbit model with a homozygous intragenic duplication in MFSD8 exhibited astrogliosis and axonal degeneration similar to human CLN7. In vitro assays reveal compromised CLN7 trafficking via mutations in key dileucine and tyrosine sorting motifs, reducing lysosomal localization and promoting proteolytic cleavage.

References

• Neurogenetics • 2009 • A novel mutation in the MFSD8 gene in late infantile neuronal ceroid lipofuscinosis. PMID:18850119
• American journal of human genetics • 2007 • The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter. PMID:17564970

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