Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S.

Amit K. Das, Carlos H R Becerra, Won Yi, Jui Yun Lu, Aristotle N. Siakotos, Krystyna E. Wisniewski, Sandra L. Hofmann

Research output: Contribution to journalArticle

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Abstract

Mutations in a newly described lysosomal enzyme, palmitoyl-protein thioesterase (PPT), were recently shown to be responsible for an autosomal recessive neurological disorder prevalent in Finland, infantile neuronal ceroid lipofuscinosis. The disease results in blindness, motor and cognitive deterioration, and seizures. Characteristic inclusion bodies (granular osmiophilic deposits [GROD]) are found in the brain and other tissues. The vast majority of Finnish cases are homozygous for a missense mutation (R122W) that severely affects PPT enzyme activity, and the clinical course in Finnish children is uniformly rapidly progressive and fatal. To define the clinical, biochemical, and molecular genetic characteristics of subjects with PPT deficiency in a broader population, we collected blood samples from U.S. and Canadian subjects representing 32 unrelated families with neuronal ceroid lipofuscinosis who had GROD documented morphologically. We measured PPT activity and screened the coding region of the PPT gene for mutations. In 29 of the families, PPT deficiency was found to be responsible for the neurodegenerative disorder, and mutations were identified in 57 out of 58 PPT alleles. One nonsense mutation (R151X) accounted for 40% of the alleles and was associated with severe disease in the homozygous state. A second mutation (T75P) accounted for 13% of the alleles and was associated with a late onset and protracted clinical course. A total of 19 different mutations were found, resulting in a broader spectrum of clinical presentations than previously seen in the Finnish population. Symptoms first appeared at ages ranging from 3 mo to 9 yr, and about half of the subjects have survived into the second or even third decades of life.

Original languageEnglish (US)
Pages (from-to)361-370
Number of pages10
JournalJournal of Clinical Investigation
Volume102
Issue number2
StatePublished - Jul 15 1998

Fingerprint

Protein Deficiency
Molecular Biology
Mutation
Neuronal Ceroid-Lipofuscinoses
Alleles
Nonsense Codon
Inclusion Bodies
Missense Mutation
Enzymes
Blindness
Finland
palmitoyl-protein thioesterase
Nervous System Diseases
Neurodegenerative Diseases
Population
Seizures
Brain
Genes

Keywords

  • Lysosomal storage disorders
  • Metabolic brain diseases
  • Molecular genetics
  • Neuronal ceroid lipofuscinosis
  • Thiolester hydrolases

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Das, A. K., Becerra, C. H. R., Yi, W., Lu, J. Y., Siakotos, A. N., Wisniewski, K. E., & Hofmann, S. L. (1998). Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. Journal of Clinical Investigation, 102(2), 361-370.

Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. / Das, Amit K.; Becerra, Carlos H R; Yi, Won; Lu, Jui Yun; Siakotos, Aristotle N.; Wisniewski, Krystyna E.; Hofmann, Sandra L.

In: Journal of Clinical Investigation, Vol. 102, No. 2, 15.07.1998, p. 361-370.

Research output: Contribution to journalArticle

Das, AK, Becerra, CHR, Yi, W, Lu, JY, Siakotos, AN, Wisniewski, KE & Hofmann, SL 1998, 'Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S.', Journal of Clinical Investigation, vol. 102, no. 2, pp. 361-370.
Das AK, Becerra CHR, Yi W, Lu JY, Siakotos AN, Wisniewski KE et al. Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. Journal of Clinical Investigation. 1998 Jul 15;102(2):361-370.
Das, Amit K. ; Becerra, Carlos H R ; Yi, Won ; Lu, Jui Yun ; Siakotos, Aristotle N. ; Wisniewski, Krystyna E. ; Hofmann, Sandra L. / Molecular genetics of palmitoyl-protein thioesterase deficiency in the U.S. In: Journal of Clinical Investigation. 1998 ; Vol. 102, No. 2. pp. 361-370.
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