TY - JOUR
T1 - Genotype-phenotype correlations in neuronal ceroid lipofuscinosis due to palmitoyl-protein thioesterase deficiency
AU - Hofmann, Sandra L.
AU - Das, Amit K.
AU - Yi, Won
AU - Lu, Jui Yun
AU - Wisniewski, Krystyna E.
N1 - Funding Information:
We thank the families who have participated in these studies, their referring physicians, the Batten Disease Support and Research Association (BDSRA; Lance Johnson, President), and Edith Dockter, coordinator of the Batten Disease Registry at the Institute for Basic Research. This study was supported by a grant from the National Institutes of Health (NS36867) and by the Indiana University Batten Disease Cell Bank (supported by NS 30171, the BDSRA, and the Children’s Brain Diseases Foundation).
PY - 1999/4
Y1 - 1999/4
N2 - 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of our previous findings, including a more detailed analysis of phenotype-genotype correlations, and present previously unpublished data concerning the clinical manifestations of the disorder in children of families with multiple affected members.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.
AB - 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.
KW - Infantile neuronal ceroid lipofuscinoses
KW - Lysosomal storage disorders
KW - Molecular genetics
KW - Thiolester hydrolases
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U2 - 10.1006/mgme.1999.2803
DO - 10.1006/mgme.1999.2803
M3 - Article
C2 - 10191107
AN - SCOPUS:0032798744
SN - 1096-7192
VL - 66
SP - 234
EP - 239
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 4
ER -