TY - JOUR
T1 - The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter
AU - Siintola, Eija
AU - Topcu, Meral
AU - Aula, Nina
AU - Lohi, Hannes
AU - Minassian, Berge A.
AU - Paterson, Andrew D.
AU - Liu, Xiao Qing
AU - Wilson, Callum
AU - Lahtinen, Ulla
AU - Anttonen, Anna Kaisa
AU - Lehesjoki, Anna Elina
N1 - Funding Information:
We thank the families with NCL, for their participation, and Drs. Christine Tranchant and Füsun Alehan, for data on patients k3 and l3, respectively. We also thank Paula Hakala, Mairi Kuris, Mervi Kuronen, Ahmed Mohamed, Hanna Olanne, Eva Reinmaa, and Teija-Tuulia Toivonen, for technical assistance; Jaana Tyynelä, for helpful advice; and Anu Jalanko, for marker antibodies. This study was supported by the Center of Excellence in Complex Disease Genetics of the Academy of Finland, the Folkhälsan Research Foundation, the Sigrid Juselius Foundation, and the European Commission (project LSHM-CT-2003-50305), to A.-E.L., and Genome Canada through the Ontario Genomics Institute, Sigrid Juselius, and Emil Aaltonen Foundations (to H.L.). E.S. and A.-K.A. are fellows of the Helsinki Biomedical Graduate School. A.D.P. holds a Canada Research Chair in the Genetics of Complex Diseases. B.A.M. holds a Canada Research Chair in Pediatric Neurogenetics.
PY - 2007/7
Y1 - 2007/7
N2 - The late-infantile-onset forms are the most genetically heterogeneous group among the autosomal recessively inherited neurodegenerative disorders, the neuronal ceroid lipofuscinoses (NCLs). The Turkish variant was initially considered to be a distinct genetic entity, with clinical presentation similar to that of other forms of late-infantile-onset NCL (LINCL), including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death. However, Turkish variant LINCL was recently found to be genetically heterogeneous, because mutations in two genes, CLN6 and CLN8, were identified to underlie the disease phenotype in a subset of patients. After a genomewide scan with single-nucleotide-polymorphism markers and homozygosity mapping in nine Turkish families and one Indian family, not linked to any of the known NCL loci, we mapped a novel variant LINCL locus to chromosome 4q28.1-q28.2 in five families. We identified six different mutations in the MFSD8 gene (previously denoted "MGC33302"), which encodes a novel polytopic 518-amino acid membrane protein that belongs to the major facilitator superfamily of transporter proteins. MFSD8 is expressed ubiquitously, with several alternatively spliced variants. Like the majority of the previously identified NCL proteins, MFSD8 localizes mainly to the lysosomal compartment. However, the function of MFSD8 remains to be elucidated. Analysis of the genome-scan data suggests the existence of at least three more genes in the remaining five families, further corroborating the great genetic heterogeneity of LINCLs.
AB - The late-infantile-onset forms are the most genetically heterogeneous group among the autosomal recessively inherited neurodegenerative disorders, the neuronal ceroid lipofuscinoses (NCLs). The Turkish variant was initially considered to be a distinct genetic entity, with clinical presentation similar to that of other forms of late-infantile-onset NCL (LINCL), including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death. However, Turkish variant LINCL was recently found to be genetically heterogeneous, because mutations in two genes, CLN6 and CLN8, were identified to underlie the disease phenotype in a subset of patients. After a genomewide scan with single-nucleotide-polymorphism markers and homozygosity mapping in nine Turkish families and one Indian family, not linked to any of the known NCL loci, we mapped a novel variant LINCL locus to chromosome 4q28.1-q28.2 in five families. We identified six different mutations in the MFSD8 gene (previously denoted "MGC33302"), which encodes a novel polytopic 518-amino acid membrane protein that belongs to the major facilitator superfamily of transporter proteins. MFSD8 is expressed ubiquitously, with several alternatively spliced variants. Like the majority of the previously identified NCL proteins, MFSD8 localizes mainly to the lysosomal compartment. However, the function of MFSD8 remains to be elucidated. Analysis of the genome-scan data suggests the existence of at least three more genes in the remaining five families, further corroborating the great genetic heterogeneity of LINCLs.
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U2 - 10.1086/518902
DO - 10.1086/518902
M3 - Article
C2 - 17564970
AN - SCOPUS:34347253609
SN - 0002-9297
VL - 81
SP - 136
EP - 146
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -