title: Two novel CLN5 mutations in a Portuguese patient with vLINCL: insights into molecular mechanisms of CLN5 deficiency.
abstract: The neuronal ceroid-lipofuscinoses are the most common neurodegenerative disorders in childhood characterized by progressive blindness, epilepsy, brain atrophy, and premature death. Based on the age at onset, disease progression and ultrastructural features three classical (infantile, late-infantile, and juvenile) and three variant late-infantile forms are generally distinguished (Finnish variant, Costa Rican variant, and epilepsy with progressive motor retardation). The Finnish variant late-infantile form has been associated with CLN5 gene defects, with only five mutations described to date. We report a patient with vLINCL/CLN5 who represents the first evidence of the disease in the Portuguese population. Mutational screening revealed the previously described missense mutation c.835G>A (D279N) inherited from the mother, and two novel mutations, c.565C>T (Q189X) and c.335G>C (R112P) from paternal and maternal inheritance, respectively. Based on data here reported: (i) the number of possible mutations in CLN5 gene is now 7; (ii) the CLN5 Portuguese case represents the third description of the disease outside northern Europe; (iii) the CLN5/mRNA expression level reduced to 45% supports the existence of one mRNA non-producing allele, further noticeable at the protein level; (iv) Western blotting data using a specific antibody to human CLN5p provided evidence for the presence of four integral membrane isoforms in human fibroblasts; (v) data from differential expression of CLN2, CLN3, and CLN5 suggest down-regulation of CLN3 gene expression in CLN2 and CLN5-deficient human patients and this observation strengths the hypothesis of functional redundancy of the CLN system.
authors.affiliation: Unidade de Enzimologia, Instituto de Genética Médica Jacinto Magalhães, Porto, Portugal.
authors.forename: C
authors.initials: C
authors.lastname: Bessa
authors.forename: C A F
authors.initials: CA
authors.lastname: Teixeira
authors.forename: M
authors.initials: M
authors.lastname: Mangas
authors.forename: A
authors.initials: A
authors.lastname: Dias
authors.forename: M C
authors.initials: MC
authors.lastname: Sá Miranda
authors.forename: A
authors.initials: A
authors.lastname: Guimarães
authors.forename: J C
authors.initials: JC
authors.lastname: Ferreira
authors.forename: N
authors.initials: N
authors.lastname: Canas
authors.forename: P
authors.initials: P
authors.lastname: Cabral
authors.forename: M G
authors.initials: MG
authors.lastname: Ribeiro
mesh_terms: D000293:Adolescent; D000626:Aminopeptidases; D001483:Base Sequence; D001921:Brain / Q000000981:diagnostic imaging; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D051907:Lysosomal Membrane Proteins; D008279:Magnetic Resonance Imaging; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics*; D011174:Portugal; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011859:Radiography; D057057:Serine Proteases; D013545:Sweat Glands / Q000648:ultrastructure; D013869:Thiolester Hydrolases; D000091346:Tripeptidyl-Peptidase 1
chemical_list: C105199:CLN3 protein, human; C113332:CLN5 protein, human; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D000091346:Tripeptidyl-Peptidase 1; D013869:Thiolester Hydrolases; C416054:PPT1 protein, human; D010450:Endopeptidases; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human