Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits

Hannah M. Mitchison, Sandra L. Hofmann, Carlos H R Becerra, Patricia B. Munroe, Brian D. Lake, Yanick J. Crow, John B P Stephenson, Ruth E. Williams, Irene L. Hofman, Peter E M Taschner, Jean Jacques Martin, Michel Philippart, Eva Andermann, Frederick Andermann, Sara E. Mole, R. Mark Gardiner, Angela M. O'Rawe

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Abstract

A subtype of neuronal ceroid lipofuscinosis (NCL) is well recognized which has a clinical course consistent with juvenile NCL (JNCL) but the ultrastructural characteristics of infantile NCL (INCL): granular osmiophilic deposits (GROD). Evidence supporting linkage of this phenotype, designated vJNCL/GROD, to the INCL region of chromosome 1p32 was demonstrated (pairwise lod score with D1S211, Z(max) = 2.63, θ = 0.00). The INCL gene, palmitoyl-protein thioesterase (PPT; CLN1), was therefore screened for mutations in 11 vJNCL/GROD families. Five mutations in the PPT gene were identified: three missense mutations, Thr75Pro, Asp79Gly, Leu219Gln, and two nonsense mutations, Leu10STOP and Arg151STOP. The missense mutation Thr75Pro accounted for nine of the 22 disease chromosomes analysed and the nonsense mutation Arg151STOP for seven. Nine out of 11 patients were shown to combine a missense mutation on one disease chromosome with a nonsense mutation on the other. Mutations previously identified in INCL were not observed in VJNCL/GROD families. Thioesterase activity in peripheral blood lymphoblast cells was found to be markedly reduced in vJNCL/GROD patients compared with controls. These results demonstrate that this subtype of JNCL is allelic to INCL and further emphasize the correlation which exists between genetic basis and ultrastructural changes in the NCLs.

Original languageEnglish (US)
Pages (from-to)291-297
Number of pages7
JournalHuman Molecular Genetics
Volume7
Issue number2
DOIs
StatePublished - Feb 1998

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Neuronal Ceroid-Lipofuscinoses
Nonsense Codon
Missense Mutation
Mutation
Chromosomes
Genes
Lod Score
Chromosomes, Human, Pair 22
Phentolamine
Blood Cells
Phenotype
palmitoyl-protein thioesterase
Proteins

ASJC Scopus subject areas

  • Genetics

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Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits. / Mitchison, Hannah M.; Hofmann, Sandra L.; Becerra, Carlos H R; Munroe, Patricia B.; Lake, Brian D.; Crow, Yanick J.; Stephenson, John B P; Williams, Ruth E.; Hofman, Irene L.; Taschner, Peter E M; Martin, Jean Jacques; Philippart, Michel; Andermann, Eva; Andermann, Frederick; Mole, Sara E.; Gardiner, R. Mark; O'Rawe, Angela M.

In: Human Molecular Genetics, Vol. 7, No. 2, 02.1998, p. 291-297.

Research output: Contribution to journalArticle

Mitchison, HM, Hofmann, SL, Becerra, CHR, Munroe, PB, Lake, BD, Crow, YJ, Stephenson, JBP, Williams, RE, Hofman, IL, Taschner, PEM, Martin, JJ, Philippart, M, Andermann, E, Andermann, F, Mole, SE, Gardiner, RM & O'Rawe, AM 1998, 'Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits', Human Molecular Genetics, vol. 7, no. 2, pp. 291-297. https://doi.org/10.1093/hmg/7.2.291
Mitchison, Hannah M. ; Hofmann, Sandra L. ; Becerra, Carlos H R ; Munroe, Patricia B. ; Lake, Brian D. ; Crow, Yanick J. ; Stephenson, John B P ; Williams, Ruth E. ; Hofman, Irene L. ; Taschner, Peter E M ; Martin, Jean Jacques ; Philippart, Michel ; Andermann, Eva ; Andermann, Frederick ; Mole, Sara E. ; Gardiner, R. Mark ; O'Rawe, Angela M. / Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits. In: Human Molecular Genetics. 1998 ; Vol. 7, No. 2. pp. 291-297.
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title = "Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits",
abstract = "A subtype of neuronal ceroid lipofuscinosis (NCL) is well recognized which has a clinical course consistent with juvenile NCL (JNCL) but the ultrastructural characteristics of infantile NCL (INCL): granular osmiophilic deposits (GROD). Evidence supporting linkage of this phenotype, designated vJNCL/GROD, to the INCL region of chromosome 1p32 was demonstrated (pairwise lod score with D1S211, Z(max) = 2.63, θ = 0.00). The INCL gene, palmitoyl-protein thioesterase (PPT; CLN1), was therefore screened for mutations in 11 vJNCL/GROD families. Five mutations in the PPT gene were identified: three missense mutations, Thr75Pro, Asp79Gly, Leu219Gln, and two nonsense mutations, Leu10STOP and Arg151STOP. The missense mutation Thr75Pro accounted for nine of the 22 disease chromosomes analysed and the nonsense mutation Arg151STOP for seven. Nine out of 11 patients were shown to combine a missense mutation on one disease chromosome with a nonsense mutation on the other. Mutations previously identified in INCL were not observed in VJNCL/GROD families. Thioesterase activity in peripheral blood lymphoblast cells was found to be markedly reduced in vJNCL/GROD patients compared with controls. These results demonstrate that this subtype of JNCL is allelic to INCL and further emphasize the correlation which exists between genetic basis and ultrastructural changes in the NCLs.",
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T1 - Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits

AU - Mitchison, Hannah M.

AU - Hofmann, Sandra L.

AU - Becerra, Carlos H R

AU - Munroe, Patricia B.

AU - Lake, Brian D.

AU - Crow, Yanick J.

AU - Stephenson, John B P

AU - Williams, Ruth E.

AU - Hofman, Irene L.

AU - Taschner, Peter E M

AU - Martin, Jean Jacques

AU - Philippart, Michel

AU - Andermann, Eva

AU - Andermann, Frederick

AU - Mole, Sara E.

AU - Gardiner, R. Mark

AU - O'Rawe, Angela M.

PY - 1998/2

Y1 - 1998/2

N2 - A subtype of neuronal ceroid lipofuscinosis (NCL) is well recognized which has a clinical course consistent with juvenile NCL (JNCL) but the ultrastructural characteristics of infantile NCL (INCL): granular osmiophilic deposits (GROD). Evidence supporting linkage of this phenotype, designated vJNCL/GROD, to the INCL region of chromosome 1p32 was demonstrated (pairwise lod score with D1S211, Z(max) = 2.63, θ = 0.00). The INCL gene, palmitoyl-protein thioesterase (PPT; CLN1), was therefore screened for mutations in 11 vJNCL/GROD families. Five mutations in the PPT gene were identified: three missense mutations, Thr75Pro, Asp79Gly, Leu219Gln, and two nonsense mutations, Leu10STOP and Arg151STOP. The missense mutation Thr75Pro accounted for nine of the 22 disease chromosomes analysed and the nonsense mutation Arg151STOP for seven. Nine out of 11 patients were shown to combine a missense mutation on one disease chromosome with a nonsense mutation on the other. Mutations previously identified in INCL were not observed in VJNCL/GROD families. Thioesterase activity in peripheral blood lymphoblast cells was found to be markedly reduced in vJNCL/GROD patients compared with controls. These results demonstrate that this subtype of JNCL is allelic to INCL and further emphasize the correlation which exists between genetic basis and ultrastructural changes in the NCLs.

AB - A subtype of neuronal ceroid lipofuscinosis (NCL) is well recognized which has a clinical course consistent with juvenile NCL (JNCL) but the ultrastructural characteristics of infantile NCL (INCL): granular osmiophilic deposits (GROD). Evidence supporting linkage of this phenotype, designated vJNCL/GROD, to the INCL region of chromosome 1p32 was demonstrated (pairwise lod score with D1S211, Z(max) = 2.63, θ = 0.00). The INCL gene, palmitoyl-protein thioesterase (PPT; CLN1), was therefore screened for mutations in 11 vJNCL/GROD families. Five mutations in the PPT gene were identified: three missense mutations, Thr75Pro, Asp79Gly, Leu219Gln, and two nonsense mutations, Leu10STOP and Arg151STOP. The missense mutation Thr75Pro accounted for nine of the 22 disease chromosomes analysed and the nonsense mutation Arg151STOP for seven. Nine out of 11 patients were shown to combine a missense mutation on one disease chromosome with a nonsense mutation on the other. Mutations previously identified in INCL were not observed in VJNCL/GROD families. Thioesterase activity in peripheral blood lymphoblast cells was found to be markedly reduced in vJNCL/GROD patients compared with controls. These results demonstrate that this subtype of JNCL is allelic to INCL and further emphasize the correlation which exists between genetic basis and ultrastructural changes in the NCLs.

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