TY - CHAP
T1 - 3 Positional candidate gene cloning of CLN1
AU - Hofmann, Sandra L.
AU - Das, Amit K.
AU - Lu, Jui Yun
AU - Soyombo, Abigail A.
PY - 2001
Y1 - 2001
N2 - Mutations in the CLN1 gene encoding palmitoyl-protein thiosterase (PPT) underlie the recessive neurodegenerative disorder, infantile Batten disease, or infantile neuronal ceroid lipofuscinosis (INCL). The CLN1 gene was mapped to chromosome 1p32 in the vicinity of a microsatellite marker HY-TM1 in a cohort of Finnish INCL families, and mapping of the PPT gene to the CLN1 critical region (and the discovery of mutations in PPT in several unrelated families) led to conclusive identification of PPT as the disease gene. PPT is a lysosomal thioesterase that removes fatty acids from fatty-acylated cysteine residues in proteins. The accumulation of fatty acyl cysteine thioesters can be reverse in INCL cells by the exogenous administration of recombinant PPT, which enters the cells through the mannose 6-phosphate receptor pathway. Over two dozen PPT mutations have been found in PPT-deficient patients worldwide. In the United States, all PPT-deficient patients show "GROD" histology but the age of onset of symptoms is later in some children due to the presence of missense mutations that result in enzymes with residual PPT activity. Now that INCL is known to be caused by a defect in a soluble lysosomal enzyme, appropriate therapies may be forthcoming. Prospects for therapy include enzyme replacement, stem cell transplantation gene therapy and metabolic therapy aimed at depleting the abnormal substrate accumulation in the disease.
AB - Mutations in the CLN1 gene encoding palmitoyl-protein thiosterase (PPT) underlie the recessive neurodegenerative disorder, infantile Batten disease, or infantile neuronal ceroid lipofuscinosis (INCL). The CLN1 gene was mapped to chromosome 1p32 in the vicinity of a microsatellite marker HY-TM1 in a cohort of Finnish INCL families, and mapping of the PPT gene to the CLN1 critical region (and the discovery of mutations in PPT in several unrelated families) led to conclusive identification of PPT as the disease gene. PPT is a lysosomal thioesterase that removes fatty acids from fatty-acylated cysteine residues in proteins. The accumulation of fatty acyl cysteine thioesters can be reverse in INCL cells by the exogenous administration of recombinant PPT, which enters the cells through the mannose 6-phosphate receptor pathway. Over two dozen PPT mutations have been found in PPT-deficient patients worldwide. In the United States, all PPT-deficient patients show "GROD" histology but the age of onset of symptoms is later in some children due to the presence of missense mutations that result in enzymes with residual PPT activity. Now that INCL is known to be caused by a defect in a soluble lysosomal enzyme, appropriate therapies may be forthcoming. Prospects for therapy include enzyme replacement, stem cell transplantation gene therapy and metabolic therapy aimed at depleting the abnormal substrate accumulation in the disease.
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U2 - 10.1016/S0065-2660(01)45004-8
DO - 10.1016/S0065-2660(01)45004-8
M3 - Chapter
C2 - 11332777
AN - SCOPUS:0035231659
SN - 0120176459
SN - 9780120176458
VL - 45
SP - 69
EP - 92
BT - Advances in Genetics
ER -