Genotype-phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency

Sandra L. Hofmann, Amit K. Das, Won Yi, Jui Yun Lu, Krystyna E. Wisniewski

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The infantile form of neuronal ceroid lipofuscinosis (NCL) has been well studied in Finland, where there is a high carrier frequency (1:70) for a single mutation in the causative gene, CLN1, or PPT. We have recently studied a group of 29 NCL subjects in the United States with palmitoyl-protein thioesterase (PPT) deficiency and described 19 different CLN1/PPT mutations in our population. In this report, we present a review of our previous findings, including a more detailed analysis of phenotype-genotype correlations, and present previously unpublished data concerning the clinical manifestations of the disorder in children of families with multiple affected members. Our studies indicate that about half of PPT-deficient patients in the United States are very similar to Finnish infants with INCL, but that a different mutation (R151X) accounts for 40% of U.S. alleles. The Finnish mutation (R122W) is rare in the United States. The other half of U.S. PPT- deficient patients develop symptoms after the age of 2 years, much later than Finnish patients. One common mutation (the 'Scottish' allele, T75P) accounts for 13% of alleles and results in a juvenile-onset phenotype that is clinically indistinguishable from JNCL with CLN3 mutations. Other rare mutations were also associated with JNCL phenotypes, such as D79G and G250V. A preliminary expression study of two of these mutant enzymes supports the conclusion that juvenile-onset NCL (JNCL with GROD) is caused by missense mutations in the PPT gene that result in mutated enzymes with residual PPT enzyme activity.

Original languageEnglish (US)
Pages (from-to)234-239
Number of pages6
JournalMolecular Genetics and Metabolism
Volume66
Issue number4
DOIs
StatePublished - Apr 1999

Fingerprint

Ceroid
Neuronal Ceroid-Lipofuscinoses
Protein Deficiency
Genetic Association Studies
Mutation
Alleles
Enzymes
Genes
Phenotype
Enzyme activity
Missense Mutation
Finland
palmitoyl-protein thioesterase

Keywords

  • Infantile neuronal ceroid lipofuscinoses
  • Lysosomal storage disorders
  • Molecular genetics
  • Thiolester hydrolases

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Endocrinology, Diabetes and Metabolism

Cite this

Genotype-phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency. / Hofmann, Sandra L.; Das, Amit K.; Yi, Won; Lu, Jui Yun; Wisniewski, Krystyna E.

In: Molecular Genetics and Metabolism, Vol. 66, No. 4, 04.1999, p. 234-239.

Research output: Contribution to journalArticle

Hofmann, Sandra L. ; Das, Amit K. ; Yi, Won ; Lu, Jui Yun ; Wisniewski, Krystyna E. / Genotype-phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency. In: Molecular Genetics and Metabolism. 1999 ; Vol. 66, No. 4. pp. 234-239.
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abstract = "The infantile form of neuronal ceroid lipofuscinosis (NCL) has been well studied in Finland, where there is a high carrier frequency (1:70) for a single mutation in the causative gene, CLN1, or PPT. We have recently studied a group of 29 NCL subjects in the United States with palmitoyl-protein thioesterase (PPT) deficiency and described 19 different CLN1/PPT mutations in our population. In this report, we present a review of our previous findings, including a more detailed analysis of phenotype-genotype correlations, and present previously unpublished data concerning the clinical manifestations of the disorder in children of families with multiple affected members. Our studies indicate that about half of PPT-deficient patients in the United States are very similar to Finnish infants with INCL, but that a different mutation (R151X) accounts for 40{\%} of U.S. alleles. The Finnish mutation (R122W) is rare in the United States. The other half of U.S. PPT- deficient patients develop symptoms after the age of 2 years, much later than Finnish patients. One common mutation (the 'Scottish' allele, T75P) accounts for 13{\%} of alleles and results in a juvenile-onset phenotype that is clinically indistinguishable from JNCL with CLN3 mutations. Other rare mutations were also associated with JNCL phenotypes, such as D79G and G250V. A preliminary expression study of two of these mutant enzymes supports the conclusion that juvenile-onset NCL (JNCL with GROD) is caused by missense mutations in the PPT gene that result in mutated enzymes with residual PPT enzyme activity.",
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