Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage

David Sleat, Rosalie M. Gin, Istvan Sohar, Krystyna Wisniewski, Susan Sklower-Brooks, Raju K. Pullarkat, David N. Palmer, Terry J. Lerner, Rose Mary Boustany, Peter Uldall, Aristotle N. Siakotos, Robert J. Donnelly, Peter Lobel

Research output: Contribution to journalArticlepeer-review

151 Scopus citations

Abstract

The late-infantile form of neuronal ceroid lipofuscinosis (LINCL) is a progressive and ultimately fatal neurodegenerative disease of childhood. The defective gene in this hereditary disorder, CLN2, encodes a recently identified lysosomal pepstatin-insensitive acid protease. To better understand the molecular pathology of LINCL, we conducted a genetic survey of CLN2 in 74 LINCL families. In 14 patients, CLN2 protease activities were normal and no mutations were identified, suggesting other forms of NCL. Both pathogenic alleles were identified in 57 of the other 60 LINCL families studied. In total, 24 mutations were associated with LINCL, comprising six splice-junction mutations, 11 missense mutations, 3 nonsense mutations, 3 small deletions, and 1 single-nucleotide insertion. Two mutations were particularly common: an intronic G→C transversion in the invariant AG of a 3' splice junction, found in 38 of 115 alleles, and a C→T transition in 32 of 115 alleles, which prematurely terminates translation at amino acid 208 of 563. An Arg→His substitution was identified, which was associated with a late age at onset and protracted clinical phenotype, in a number of other patients originally diagnosed with juvenile NCL.

Original languageEnglish (US)
Pages (from-to)1511-1523
Number of pages13
JournalAmerican Journal of Human Genetics
Volume64
Issue number6
DOIs
StatePublished - 1999

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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