CLN6 – Neuronal ceroid lipofuscinosis

CLN6 encodes a multi‐pass endoplasmic reticulum (ER) membrane protein essential for lysosomal homeostasis in the central nervous system. Biallelic loss‐of‐function variants in CLN6 underlie autosomal recessive neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder marked by progressive psychomotor decline, myoclonus, seizures, visual impairment and early death (PMID:23180398).

Inheritance is autosomal recessive, with consanguineous pedigrees reporting homozygous CLN6 variants segregating with disease. In one large Moroccan family, three affected sibs harbored the recurrent p.Ile154del variant (PMID:23180398). A single‐center cohort of 97 CLN6 patients from 86 families confirmed 45 unique variants and extensive multi‐family segregation, reaching the ClinGen genetic evidence cap (PMID:35505348).

The CLN6 variant spectrum includes missense, in‐frame deletions, splice‐site, frameshift and structural alleles. Founder alleles such as p.Ile154del are prevalent in Portuguese and Moroccan populations, and c.316dup (p.Arg106ProfsTer26) in Pakistani families. We report c.509A>G (p.Tyr170Cys) as a representative missense change identified in adult‐onset Kufs disease (PMID:28587997).

Clinical presentation spans late‐infantile through adult‐onset forms: seizures (HP:0001250), cortical myoclonus (HP:0001336), ataxia (HP:0001251), progressive psychomotor deterioration (HP:0007272) and visual impairment (HP:0000505). Onset typically occurs between 2 and 8 years for LINCL, with milder juvenile or Kufs variants manifesting in adolescence or adulthood.

Functional studies demonstrate ER retention of CLN6, abnormal proteasome‐dependent degradation of mutant proteins, and impaired lysosomal turnover of endocytosed enzymes. CLN6‐deficient fibroblasts show reduced degradation of arylsulfatase A, and Cln6(nclf) mice recapitulate human motor, cognitive and retinal decline with cortical interneuron loss and glial activation (PMID:15010453; PMID:24223841). Interaction with CRMP‐2 implicates disrupted neurite maturation in pathogenesis (PMID:19235893).

Collectively, extensive genetic, segregation and functional data establish a definitive gene‐disease relationship between CLN6 and NCL. Early genetic testing facilitates diagnosis, informs carrier screening in high‐risk populations, and supports emerging therapeutic strategies.

References

• Indian Journal of Pediatrics | 2013 | CLN6 p.I154del mutation causing late infantile neuronal ceroid lipofuscinosis in a large consanguineous Moroccan family. PMID:23180398
• Orphanet Journal of Rare Diseases | 2022 | Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center. PMID:35505348
• The Journal of Biological Chemistry | 2004 | Defective endoplasmic reticulum-resident membrane protein CLN6 affects lysosomal degradation of endocytosed arylsulfatase A. PMID:15010453
• PLoS One | 2013 | A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease. PMID:24223841
• Journal of Neuroscience Research | 2009 | Protein product of CLN6 gene responsible for variant late-onset infantile neuronal ceroid lipofuscinosis interacts with CRMP-2. PMID:19235893

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