CLN3 – Juvenile Neuronal Ceroid Lipofuscinosis

Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) is an autosomal recessive lysosomal storage disorder characterized by progressive vision loss, seizures, dementia, and motor decline and is caused by biallelic mutations in the CLN3 gene (HGNC:2074), which maps to chromosome 16p12.1 (PMID:7553855).

Extensive genetic studies demonstrate that a 1.02 kb deletion affecting exons 7–8 accounts for ~85% of CLN3 disease alleles, with over 188 unrelated JNCL patients screened for this and other variants, including missense, nonsense, splice-site, and small indels (PMID:9311735). One recurrent missense variant, c.883G>A (p.Glu295Lys), has been observed in both classic and protracted phenotypes and disrupts a conserved residue critical for protein function (PMID:9450775).

Segregation analyses in multiple families, including a consanguineous Lebanese kindred with five affected siblings homozygous for c.597C>A (p.Tyr199Ter) and a sibling pair with compound heterozygosity for the 1 kb deletion and c.883G>A (p.Glu295Lys), confirm autosomal recessive inheritance and complete co-segregation of CLN3 variants with disease (PMID:19489875).

Functional assays in patient-derived cells and animal models reveal that loss of CLN3 impairs lysosomal and endosomal trafficking, defective synaptic vesicle transport, astrocyte metabolic dysregulation, and reduced autophagosome–lysosome fusion. Cln3Δex1- mouse models accumulate autofluorescent storage material, display retinal degeneration, motor deficits, and premature death, reflecting human pathology (PMID:10332042; PMID:29135436).

Mechanistically, CLN3 appears to modulate endosome-to-TGN sorting via retromer and Rab7A interactions, and its deficiency leads to defective lysosomal receptor trafficking and synaptic dysfunction, supporting a loss-of-function disease model.

Collectively, the breadth of genetic and experimental evidence establishes a definitive gene–disease association for CLN3-related JNCL. Early molecular diagnosis enables prenatal testing, genetic counseling, and supports emerging therapies focused on restoring CLN3 function.

References

• Cell • 1995 • Isolation of a novel gene underlying Batten disease, CLN3. PMID:7553855
• American journal of human genetics • 1997 • Spectrum of mutations in the Batten disease gene, CLN3. PMID:9311735
• Annals of neurology • 1998 • Compound heterozygous genotype is associated with protracted juvenile neuronal ceroid lipofuscinosis. PMID:9450775
• Clinical genetics • 2009 • Protracted course of juvenile ceroid lipofuscinosis associated with a novel CLN3 mutation (p.Y199X). PMID:19489875
• Human molecular genetics • 1999 • Defective intracellular transport of CLN3 is the molecular basis of Batten disease (JNCL). PMID:10332042
• eLife • 2017 • Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis. PMID:29135436

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