Alternative titles; symbols
HGNC Approved Gene Symbol: MFSD8
Cytogenetic location: 4q28.2 Genomic coordinates (GRCh38) : 4:127,917,732-127,965,963 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
4q28.2 | Ceroid lipofuscinosis, neuronal, 7 | 610951 | Autosomal recessive | 3 |
Macular dystrophy with central cone involvement | 616170 | Autosomal recessive | 3 |
Siintola et al. (2007) identified a novel gene, major facilitator superfamily domain-containing protein-8 (MFSD8), through positional cloning following homozygosity mapping in Turkish families with late infantile-onset neuronal ceroid lipofuscinosis (CLN7; 610951). The MFSD8 gene was predicted to encode a 518-amino acid protein of approximately 58 kD with 12 predicted transmembrane domains. Pfam analysis of the MFSD8 amino acid sequence showed that it contains an MFS domain at amino acid positions 42 through 477 and a sugar (and other) transporter domain at amino acid positions 72 through 147. MFSD8 appeared to be evolutionarily conserved, since a BLAST search returned several homologs for MFSD8 in different species. MFSD8 localizes mainly to the lysosomal compartment. Northern blot analysis detected an approximately 5-kb MFSD8 transcript expressed at very low levels in all tissues tested. Northern blot and EST database analysis suggested the presence of alternative splice variants.
Siintola et al. (2007) identified the MFSD8 gene in chromosome 4q28.1-q28.2, within a region identified by homozygosity mapping.
Von Kleist et al. (2019) developed an immortalized granule neuron progenitor cell line (Cln7 -/- Cb), which was derived from the cerebellum of Cln7 knockout mice. The Cln7 -/- Cb cells demonstrated enlarged late endosomes and lysosomes, impaired radial/outward movement of late endosomes and lysosomes with a preferential perinuclear localization, and decreased lysosomal exocytosis. Furthermore, amino acid and serum deprivation for 8 hours resulted in decreased Akt ser473 phosphorylation and enhanced cell death compared to wildtype cells. Von Kleist et al. (2019) concluded that CLN7 is involved in mTOR-regulated mechanisms including lysosome movement and the cellular response to nutrient deprivation.
Neuronal Ceroid Lipofuscinosis 7
The neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurodegenerative lysosomal storage disorders characterized by the accumulation of autofluorescent storage material in many cell types, including neurons. Within the NCLs, the late infantile-onset forms (LINCL) are the most genetically heterogeneous. Siintola et al. (2007) performed a genomewide scan with single-nucleotide polymorphism (SNP) markers and homozygosity mapping in 9 Turkish families and 1 Indian family who were not linked to any known NCL locus and mapped a vLINCL locus (CLN7; 610951) to chromosome 4q28.1-q28.2 in 5 families. The authors identified 6 different mutations in the MFSD8 gene (see, e.g., 611124.0001-611124.0003 and 611124.0010). Analysis of the genome-scan data suggested the existence of at least 3 more genes in the remaining 5 families, further corroborating the great genetic heterogeneity of LINCLs.
In affected individuals of a consanguineous Egyptian family with CLN7, Stogmann et al. (2009) identified a homozygous mutation in the MFSD8 gene (611124.0004).
In 32 of 80 patients from 75 families with late-infantile onset CLN, Kousi et al. (2009) identified 10 mutations in the MFSD8 gene, including 8 novel mutations (see, e.g., 611124.0006-611124.0007). Although most of the patients were of Turkish origin, many were from other regions, including India, the Netherlands, Italy, and Czech Republic. The phenotype was mostly homogeneous, with onset between 1.5 and 5 years, developmental regression, seizures, mental and motor regression, speech impairments, ataxia, visual failure, and myoclonus. Most of the mutations were private, found only in a single family. One mutation, T294K (611124.0006), was found in 14 Roma patients from 12 families with CLN7 from the former Czechoslovakia. Haplotype analysis was consistent with a founder effect. In addition, all known CLN loci were excluded in Turkish patients from 35 families with late-infantile CLN, indicating genetic heterogeneity.
In 9 (39%) of 23 children with late infantile-onset CLN, Aiello et al. (2009) identified homozygosity or compound heterozygosity for pathogenic mutations in MFSD8 (see, e.g., 611124.0001, 611124.0009, and 611124.0011-611124.0012).
Macular Dystrophy With Central Cone Involvement
In 5 Dutch sibs who had macular dystrophy with central cone involvement (CCMD; 616170), Roosing et al. (2015) identified compound heterozygosity for a missense mutation (E336Q; 611124.0008) and a nonsense mutation (E381X; 611124.0009) in the MFSD8 gene. In an unrelated Dutch man with CCMD, they identified compound heterozygosity for the E336Q mutation and a splice site mutation (611124.0010). None of the Dutch patients had extraocular features. Roosing et al. (2015) hypothesized that E336Q represents a hypomorphic variant and proposed a threshold model in which residual activity of MFSD8 suffices for proper function in all organs except the eye, resulting in nonsyndromic eye disease.
Ashwini et al. (2016) performed neurologic evaluations on 4 unrelated client-owned Chihuahua dogs from Japan, Italy, and England that exhibited progressive neurologic signs consistent with a diagnosis of NCL. Brain and in some cases also retinal and heart tissues were examined postmortem for the presence of lysosomal storage bodies characteristic of NCL. The affected dogs exhibited massive accumulation of autofluorescent lysosomal storage bodies in the brain, retina, and heart accompanied by brain atrophy and retinal degeneration. The dogs were screened for known canine NCL mutations that had been reported in a variety of dog breeds. All 4 dogs were homozygous for the MFSD8 single-basepair deletion (c.843delT) previously associated with NCL in a Chinese Crested dog and in 2 affected littermate Chihuahuas from Scotland. The dogs were all homozygous for the normal alleles at the other genetic loci known to cause different forms of canine NCL. The MFSD8 c.843delT mutation was not present in 57 Chihuahuas that were either clinically normal or suffered from unrelated diseases or in 1761 unaffected dogs representing 186 other breeds. Based on these data Ashwini et al. (2016) considered it almost certain that the MFSD8 c.843delT mutation is the cause of NCL in Chihuahuas. Because the disorder occurred in widely separated geographic locations or in unrelated dogs from the same country, it is likely that the mutant allele is widespread among Chihuahuas. Ashwini et al. (2016) suggested that genetic testing for this mutation in other Chihuahuas is therefore likely to identify intact dogs with the mutant allele that could be used to establish a research colony that could be used to test potential therapeutic interventions for the corresponding human disease.
In a Turkish patient with late infantile-onset neuronal ceroid lipofuscinosis (CLN7; 610951) studied by Topcu et al. (2004), Siintola et al. (2007) identified a homozygous missense mutation in exon 10 of the MFSD8 gene: a 929G-A transition resulting in a gly310-to-asp (G310D) substitution.
In a 14-year-old Italian girl with CLN7, Aiello et al. (2009) identified compound heterozygosity for the G310D mutation and a splice site mutation (611124.0011) in MFSD8.
In a Turkish patient with late infantile-onset neuronal ceroid lipofuscinosis (CLN7; 610951) studied by Topcu et al. (2004), Siintola et al. (2007) identified a homozygous 1286G-A transition in exon 12 of the MFSD8 gene that resulted in a gly429-to-asp (G429D) substitution.
In a patient with a late infantile-onset form of neuronal ceroid lipofuscinosis (CLN7; 610951) from India, Siintola et al. (2007) identified homozygosity for an 894T-G transversion in exon 10 of the MFSD8 gene that gave rise to a truncated protein (tyr298 to ter; Y298X).
In affected members of a consanguineous Egyptian family with late-infantile neuronal ceroid lipofuscinosis (CLN7; 610951), Stogmann et al. (2009) identified a homozygous 362A-G transition in exon 5 of the MFSD8 gene, resulting in a tyr121-to-cys (Y121C) substitution in the third transmembrane domain. All patients showed onset around age 5 years of seizures and progressive decline in psychomotor function. None had visual abnormalities. The unaffected parents were each heterozygous for the mutation. The mutation was not identified in 50 Egyptian and 200 Austrian controls.
In 3 affected members of a consanguineous Saudi family with late-infantile neuronal ceroid lipofuscinosis (CLN7; 610951), Aldahmesh et al. (2009) identified a homozygous 1398C-T transition in exon 12 of the MFSD8 gene, resulting in a pro412-to-leu (P412L) substitution in a highly conserved residue. The mutation was not found in 240 control Saudi chromosomes. The proband developed poor vision at age 6 years and had onset of focal seizures with secondary generalization 1 year later. His vision deteriorated to blindness by age 7.5, and he had declining cognitive function. By age 10, he had minimal verbal communication and retinitis pigmentosa. There was no evidence of ultrastructural deposits of NCL on conjunctival biopsy. A 14-year-old brother and an 18-year-old half-sister had a similar presentation.
In 14 Roma patients from 12 families with neuronal ceroid lipofuscinosis (CLN7; 610951) from the former Czechoslovakia, Kousi et al. (2009) identified a homozygous 881C-A transversion in exon 10 of the MFSD8 gene, resulting in a thr294-to-lys (T294K) substitution in a highly conserved residue in the predicted seventh lumenal loop of the protein. The T294K mutation was also identified in 3 patients of Turkish origin and in 1 of Czech origin, and was not identified in 200 control chromosomes. Immunofluorescence analysis showed colocalization of the mutant protein with the lysosomal marker LAMP1 (153330), suggesting that the defect is functional. The phenotype was characterized by late-infantile onset, developmental regression, seizures, visual failure, and ataxia. Haplotype analysis of the Roma patients was consistent with a founder effect.
In a Dutch patient with a protracted course of neuronal ceroid lipofuscinosis (CLN7; 610951), Kousi et al. (2009) identified a homozygous 2-bp deletion/2-bp insertion (468delTGinsCC) in exon 6 of the MFSD8 gene, resulting in an ala157-to-pro (A157P) substitution in the fourth cytosolic loop. The mutation substituted a neutral nonpolar alanine with another neutral nonpolar proline. The patient presented at age 11 years with visual failure. He had motor impairment and seizures in his mid-twenties, followed by mental and speech regression in his thirties, and loss of independent ambulation at age 39. Kousi et al. (2009) postulated that the mild impact of the mutation on amino acid substitution may have contributed to the later onset and milder course of the disorder in this patient. Importantly, patients with later onset should still be considered to have mutations in the MFSD8 gene.
In 5 Dutch sibs who had macular dystrophy with central cone involvement (CCMD; 616170), Roosing et al. (2015) identified compound heterozygosity for 2 mutations in the MFSD8 gene: a c.1106G-C transversion, resulting in a glu336-to-gln (E336Q; rs150418024) substitution at a highly conserved residue in the cytoplasmic region, and a nonsense mutation (E381X; 611124.0009). The mutations segregated with disease in the family. In an unrelated 62-year-old Dutch man with CCMD, they identified compound heterozygosity for E336Q and a splice site mutation in MFSD8 (611124.0010). Although neither truncating mutation was found in exome variant databases, the E336Q missense variant was present in 1 (0.3%) of 302 alleles from ethnically matched controls, in 9 (0.21%) of 4,190 alleles in an in-house exome database, and in 25 (0.19%) of 12,006 European American alleles in the Exome Variant Server database; it was not found in 2,184 alleles in the 1000 Genomes Project database. Screening for E336Q in a cohort of patients with inherited maculopathy and cone disorders (22 with achromatopsia, 110 with cone dystrophy, and 112 with cone-rod dystrophy) identified 4 patients carrying the variant in heterozygous state; sequence analysis of MFSD8 did not identify a second variant on the other allele. Regarding the lack of neurologic features in the Dutch patients carrying 2 MFSD8 mutations, Roosing et al. (2015) hypothesized that E336Q represents a hypomorphic variant and proposed a threshold model in which residual activity of MFSD8 suffices for proper function in all organs except the eye, resulting in nonsyndromic eye disease.
Neuronal Ceroid Lipofuscinosis 7
In a 10-year-old boy from southeastern France with late infantile-onset neuronal ceroid lipofuscinosis (CLN7; 610951), Aiello et al. (2009) identified compound heterozygosity for 2 nonsense mutations in the MFSD8 gene: a c.1141G-T transversion in exon 12, resulting in a glu381-to-ter (E381X) substitution, and a c.1444C-T transition in exon 13, resulting in an arg482-to-ter (R482X; 611124.0012) substitution.
Macular Dystrophy with Central Cone Involvement
In 5 Dutch sibs who had macular dystrophy with central cone involvement (CCMD; 616170), Roosing et al. (2015) identified compound heterozygosity for a missense mutation (E336Q; 611124.0008) and the E381X nonsense mutation. The latter mutation was not found in 4,190 alleles from an in-house exome database, or in 12,006 alleles from the Exome Variant Server or 2,184 alleles from the 1000 Genomes Project databases. Noting that the Dutch patients exhibited no extraocular features, Roosing et al. (2015) hypothesized that the E336Q missense mutation represents a hypomorphic variant and proposed a threshold model in which residual activity of MFSD8 suffices for proper function in all organs except the eye, resulting in nonsyndromic eye disease.
Neuronal Ceroid Lipofuscinosis 7
In a 5.5-year-old Turkish girl with late infantile-onset neuronal ceroid lipofuscinosis (CLN7; 610951), Siintola et al. (2007) identified homozygosity for a c.1102G-C transversion in exon 11 of the MFSD8 gene, resulting in an asp368-to-his (D368H) substitution at a highly conserved residue or a splicing defect. The mutation, which segregated with disease in the family, was not found in 212 Turkish or 92 CEPH control chromosomes. Siintola et al. (2007) noted that the mutation was located at the exon-intron junction and thus might affect transcript splicing, but RNA was unavailable for analysis. The patient had a history of seizures and delayed speech development as well as worsening ataxia over the previous 6 months, with frequent falls. Examination revealed an ataxic gait with abnormal cerebellar tests; she was able to speak slowly. Brain MRI showed cerebellar atrophy.
Kim et al. (2019) reported a 6-year-old girl with insidious onset of blindness, ataxia, seizures, and developmental regression, diagnosed as CLN7, who was compound heterozygous for the 1102G-C mutation, inherited from her father, and a complex SINE-VNTR-Alu insertion inherited from her mother. Kim et al. (2019) described development and use of an antisense oligonucleotide (ASO) drug, milasen, modeled after nusinersen, used to treat spinal muscular atrophy. Intrathecal injection of the ASO in an escalating dose resulted in decreased frequency and duration of seizures.
Macular Dystrophy with Central Cone Involvement
In a 62-year-old Dutch man who had macular dystrophy with central cone involvement (CCMD; 616170), Roosing et al. (2015) identified compound heterozygosity for a missense mutation (E336Q; 611124.0008) and the c.1102G-C transversion in the MFSD8 gene. Analysis of the effect of the latter mutation, which occurs at the last nucleotide of exon 11, revealed that it causes skipping of exon 11 and is thus predicted to result in a truncated protein (Lys333LysfsTer3). A transcript lacking exon 11 was observed in a control sample, suggesting that this event also occurs naturally; however, the ratio of abnormal to normal transcript in the patient was 4:1, whereas in the control it was 1:1. The splice site mutation was not found in 4,190 alleles from an in-house exome database, or in 12,006 alleles from the Exome Variant Server or 2,184 alleles from the 1000 Genomes Project databases. Noting that the Dutch patient exhibited no extraocular features, Roosing et al. (2015) hypothesized that the E336Q missense mutation represents a hypomorphic variant and proposed a threshold model in which residual activity of MFSD8 suffices for proper function in all organs except the eye, resulting in nonsyndromic eye disease.
In 3 unrelated children of Italian origin with late infantile-onset neuronal ceroid lipofuscinosis (CLN7; 610951), Aiello et al. (2009) identified compound heterozygosity for a 1-bp insertion (c.863+3_4insT) in intron 9 of the MFSD8 gene and 3 different missense mutations in MFSD8 (e.g., G310D; 611124.0001). Analysis of the effect of the 1-bp splice site insertion in patient fibroblasts showed transcripts lacking exon 8 or exons 8 and 9 in addition to wildtype transcript.
For discussion of the arg482-to-ter (R482X) mutation in the MFSD8 gene that was found in compound heterozygous state in a patient with late infantile-onset neuronal ceroid lipofuscinosis (CLN7; 610951) by Aiello et al. (2009), see 611124.0009.
Aiello, C., Terracciano, A., Simonati, A., Discepoli, G., Cannelli, N., Claps, D., Crow, Y. J., Bianchi, M., Kitzmuller, C., Longo, D., Tavoni, A., Franzoni, E., and 10 others. Mutations in MFSD8/CLN7 are a frequent cause of variant-late infantile neuronal ceroid lipofuscinosis. Hum. Mutat. 30: E530-E540, 2009. Note: Electronic Article. [PubMed: 19177532] [Full Text: https://doi.org/10.1002/humu.20975]
Aldahmesh, M. A., Al-Hassnan, Z. N., Aldosari, M., Alkuraya, F. S. Neuronal ceroid lipofuscinosis caused by MFSD8 mutations: a common theme emerging. Neurogenetics 10: 307-311, 2009. [PubMed: 19277732] [Full Text: https://doi.org/10.1007/s10048-009-0185-1]
Ashwini, A., D'Angelo, A., Yamato, O., Giordano, C., Cagnotti, G., Harcourt-Brown, T., Mhlanga-Mutangadura, T., Guo, J., Johnson, G. S., Katz, M. L. Neuronal ceroid lipofuscinosis associated with an MFSD8 mutation in Chihuahuas. Molec. Genet. Metab. 118: 326-332, 2016. [PubMed: 27211611] [Full Text: https://doi.org/10.1016/j.ymgme.2016.05.008]
Kim, J., Hu, C., Moufawad El Achkar, C., Black, L. E., Douville, J., Larson, A., Pendergast, M. K., Goldkind, S. F., Lee, E. A., Kuniholm, A., Soucy, A., Vaze, J., and 36 others. Patient-customized oligonucleotide therapy for a rare genetic disease. New Eng. J. Med. 381: 1644-1652, 2019. [PubMed: 31597037] [Full Text: https://doi.org/10.1056/NEJMoa1813279]
Kousi, M., Siintola, E., Dvorakova, L., Vlaskova, H., Turnbull, J., Topcu, M., Yuksel, D., Gokben, S., Minassian, B. A., Elleder, M., Mole, S. E., Lehesjoki, A.-E. Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis. Brain 132: 810-819, 2009. [PubMed: 19201763] [Full Text: https://doi.org/10.1093/brain/awn366]
Roosing, S., van den Born, L. I., Sangermano, R., Banfi, S., Koenekoop, R. K., Zonneveld-Vrieling, M. N., Klaver, C. C. W., van Lith-Verhoeven, J. J. C., Cremers, F. P. M., den Hollander, A. I., Hoyng, C. B. Mutations in MFSD8, encoding a lysosomal membrane protein, are associated with nonsyndromic autosomal recessive macular dystrophy. Ophthalmology 122: 170-179, 2015. [PubMed: 25227500] [Full Text: https://doi.org/10.1016/j.ophtha.2014.07.040]
Siintola, E., Topcu, M., Aula, N., Lohi, H., Minassian, B. A., Paterson, A. D., Liu, X.-Q., Wilson, C., Lahtinen, U., Anttonen, A.-K., Lehesjoki, A.-E. The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter. Am. J. Hum. Genet. 81: 136-146, 2007. [PubMed: 17564970] [Full Text: https://doi.org/10.1086/518902]
Stogmann, E., El Tawil, S., Wagenstaller, J., Gaber, A., Edris, S., Abdelhady, A., Assem-Hilger, E., Leutmezer, F., Bonelli, S., Baumgartner, C., Zimprich, F., Strom, T. M., Zimprich, A. A novel mutation in the MFSD8 gene in late infantile neuronal ceroid lipofuscinosis. Neurogenetics 10: 73-77, 2009. [PubMed: 18850119] [Full Text: https://doi.org/10.1007/s10048-008-0153-1]
Topcu, M., Tan, H., Yalnizoglu, D., Usubutun, A., Saatci, I., Aynaci, M., Anlar, B., Topaloglu, H., Turanli, G., Kose, G., Aysun, S. Evaluation of 36 patients from Turkey with neuronal ceroid lipofuscinosis: clinical, neurophysiological, neuroradiological and histopathologic studies. Turk. J. Pediat. 46: 1-10, 2004. [PubMed: 15074367]
von Kleist, L., Ariunbat, K., Braren, I., Stauber, T., Storch, S., Danyukova, T. A newly generated neuronal cell model of CLN7 disease reveals aberrant lysosome motility and impaired cell survival. Molec. Genet. Metab. 126: 196-205, 2019. [PubMed: 30301600] [Full Text: https://doi.org/10.1016/j.ymgme.2018.09.009]