Abstract
Neuronal ceroid lipofuscinoses (NCL) are lysosomal storage disorders and constitute the most common group of progressive neurodegenerative diseases in childhood. Most NCLs are inherited in a recessive manner and are clinically characterised by a variable age at onset, epileptic seizures, psychomotor decline, visual impairment and premature death. To date, eight causative genes have been identified to underlie various clinical forms of NCL. We performed a genome-wide linkage analysis followed by sequencing the recently described NCL gene MFSD8 in three affected and three unaffected members of a consanguineous Egyptian family with an autosomal recessively inherited progressive neurodegenerative disorder. The clinical picture of the patients was compatible with a late infantile NCL (LINCL); however, impairment of the visual system was not a cardinal symptom in the respective family. By linkage analysis, we identified two putative loci on chromosome 1p36.11-p35.1 and 4q28.1-q28.2. The latter locus (4q28.1-q28.2) contained the MFSD8 gene, comprising a novel homozygous missense mutation in exon 5 (c.362a>g /p.Tyr121Cys), which segregated with the disease in the three affected sibs. We describe a novel mutation in the previously identified MFSD8 gene in a family with a common phenotype of LINCL, but no clinical report of vision loss. Our results enlarge the mutational and perhaps the nosological spectrum of one of the recently identified subtypes of NCL, called CLN7.
Similar content being viewed by others
References
Haltia M (2006) The neuronal ceroid-lipofuscinoses: from past to present. Biochim Biophys Acta 1762(10):850–856
Haltia M (2003) The neuronal ceroid-lipofuscinoses. J Neuropathol Exp Neurol 62(1):1–13
Santavuori P, Lauronen L, Kirveskari K, Aberg L, Sainio K (2000) Neuronal ceroid lipofuscinoses in childhood. Suppl Clin Neurophysiol 53:443–451
Goebel HH, Wisniewski KE (2004) Current state of clinical and morphological features in human NCL. Brain Pathol 14(1):61–69
Wisniewski KE, Zhong N, Philippart M (2001) Pheno/genotypic correlations of neuronal ceroid lipofuscinoses. Neurology 57(4):576–581
Siintola E, Lehesjoki AE, Mole SE (2006) Molecular genetics of the NCLs—status and perspectives. Biochim Biophys Acta 1762(10):857–864
Mole SE (2006) Neuronal ceroid lipofuscinoses (NCL). Eur J Paediatr Neurol 10(5–6):255–257. doi:10.1016/j.ejpn.2006.08.009
Mole SE (2004) The genetic spectrum of human neuronal ceroid-lipofuscinoses. Brain Pathol 14(1):70–76
Williams RE, Aberg L, Autti T, Goebel HH, Kohlschutter A, Lonnqvist T (2006) Diagnosis of the neuronal ceroid lipofuscinoses: an update. Biochim Biophys Acta 1762(10):865–872
Steinfeld R, Heim P, von Gregory H, Meyer K, Ullrich K, Goebel HH et al (2002) Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations. Am J Med Genet 112(4):347–354. doi:10.1002/ajmg.10660
Zhong N, Moroziewicz DN, Ju W, Jurkiewicz A, Johnston L, Wisniewski KE et al (2000) Heterogeneity of late-infantile neuronal ceroid lipofuscinosis. Genet Med 2(6):312–318. doi:10.1097/00125817-200011000-00002
Siintola E, Topcu M, Aula N, Lohi H, Minassian BA, Paterson AD et al (2007) The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter. Am J Hum Genet 81(1):136–146. doi:10.1086/518902
Topcu M, Tan H, Yalnizoglu D, Usubutun A, Saatci I, Aynaci M et al (2004) Evaluation of 36 patients from Turkey with neuronal ceroid lipofuscinosis: clinical, neurophysiological, neuroradiological and histopathologic studies. Turk J Pediatr 46(1):1–10
Ruschendorf F, Nurnberg P (2005) ALOHOMORA: a tool for linkage analysis using 10K SNP array data. Bioinformatics 21(9):2123–2125. doi:10.1093/bioinformatics/bti264
Gudbjartsson DF, Jonasson K, Frigge ML, Kong A (2000) Allegro, a new computer program for multipoint linkage analysis. Nat Genet 25(1):12–13. doi:10.1038/75514
Bessa C, Teixeira CA, Dias A, Alves M, Rocha S, Lacerda L et al (2008) CLN2/TPP1 deficiency: the novel mutation IVS7-10A>G causes intron retention and is associated with a mild disease phenotype. Mol Genet Metab 93(1):66–73. doi:10.1016/j.ymgme.2007.08.124
Chang M, Cooper JD, Sleat DE, Cheng SH, Dodge JC, Passini MA et al (2008) Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis. Mol Ther 16(4):649–656. doi:10.1038/mt.2008.9
Disclosure
The authors report no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplemental Fig. 1
Protein alignment of the sequence encompassing the Y121C mutation indicate conservation of the Tyrosine residue among the following: Homo sapiens (NP_689991.1); Pan troglodytes (XP_526685.2); Mus musculus (NP_082416.2); Gallus gallus (XP_420463.1); Drosophila melanogaster (NP_648107.3); Danio rerio (NP_001038513.1). (GIF 5.05 KB)
Rights and permissions
About this article
Cite this article
Stogmann, E., El Tawil, S., Wagenstaller, J. et al. A novel mutation in the MFSD8 gene in late infantile neuronal ceroid lipofuscinosis. Neurogenetics 10, 73–77 (2009). https://doi.org/10.1007/s10048-008-0153-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10048-008-0153-1