title: Novel mutations in the CLN6 gene causing a variant late infantile neuronal ceroid lipofuscinosis.
abstract: The neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of autosomal recessive neurodegenerative diseases comprising Batten and other related diseases plus numerous variants. They are characterized by progressive neuronal cell death. The CLN6 gene was recently identified, mutations in which cause one of the variant late infantile forms of NCL (vLINCL). We describe four novel mutations in the CLN6 gene. This brings the total number of CLN6 mutations known to 11 in 38 families. This suggests that the CLN6 gene may be highly mutable. An American patient of Irish/French/Native American origin was heterozygous for a 4-bp insertion (c.267_268insAACG) in exon 3. The other allele had a point mutation (c.898T>C) in exon 7 resulting in a W300R amino acid change. Two Trinidadian siblings of Indian origin were homozygous for a mutation at the 5' donor splice site of exon 4 (IVS4+1G>T), affecting the first base of the invariant GT at the beginning of intron 4. The fourth novel mutation, a double deletion of 4 bp and 1 bp in exon 7 (c.829_832delGTCG;c.837delG), was identified in a Portuguese patient heterozygous for the I154del Portuguese CLN6 mutation. Four of the 11 mutations identified are in exon 4. Three Portuguese patients with clinical profiles similar to CLN6 patients without defects in CLN6 or other known NCL genes are described. We conclude the following: 1) the CLN6 gene may be a highly mutable gene; 2) exon 4 must code for a segment of the protein crucial for function; 3) vLINCL disease in Portugal is genetically heterogeneous; 4) the I154del accounts for 81.25% of affected CLN6 Portuguese alleles; and 5) three vLINCL Portuguese patients may have defects in a new NCL gene.
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Carla A
authors.initials: CA
authors.lastname: Teixeira
authors.forename: Janice
authors.initials: J
authors.lastname: Espinola
authors.forename: Liang
authors.initials: L
authors.lastname: Huo
authors.forename: Johannes
authors.initials: J
authors.lastname: Kohlschütter
authors.forename: Dixie-Ann
authors.initials: DA
authors.lastname: Persaud Sawin
authors.forename: Berge
authors.initials: B
authors.lastname: Minassian
authors.forename: Carlos J P
authors.initials: CJ
authors.lastname: Bessa
authors.forename: A
authors.initials: A
authors.lastname: Guimarães
authors.forename: Dietrich A
authors.initials: DA
authors.lastname: Stephan
authors.forename: Maria Clara
authors.initials: MC
authors.lastname: Sá Miranda
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: Maria Gil
authors.initials: MG
authors.lastname: Ribeiro
authors.forename: Rose-Mary N
authors.initials: RM
authors.lastname: Boustany
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D006801:Humans; D007223:Infant; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics*
chemical_list: C447500:CLN6 protein, human; D008565:Membrane Proteins; D004247:DNA