Alternative titles; symbols
HGNC Approved Gene Symbol: SCYL1
SNOMEDCT: 1187643003;
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38) : 11:65,525,083-65,538,704 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.1 | Spinocerebellar ataxia, autosomal recessive 21 | 616719 | Autosomal recessive | 3 |
The SCYL1 gene encodes a protein that belongs to a family of catalytically inactive protein kinases. It represents an important protein at the interface between the Golgi apparatus and the membrane-trafficking machinery mediated by coatomer (COPI)-coated vesicles, and is likely involved in intracellular transport processes (summary by Schmidt et al., 2015).
Liu et al. (2000) cloned mouse Scyl1, which they called p105, from an adipocyte cell line cDNA library. The deduced 806-amino acid protein has a calculated molecular mass of about 89 kD. Scyl1 shares significant sequence similarity with kinases, but its putative kinase domain lacks subdomain 1 of the 12 characteristic subdomains, and it is missing highly conserved residues in other subdomains, suggesting that Scyl1 is not a functional kinase. Western blot analysis of mouse tissues found that Scyl1 has an apparent molecular mass of about 105 kD and is present in all tissues examined. Western blot analysis of subcellular fractions indicated that mouse Scyl1 is primarily cytosolic and that it is present in low density microsomes.
By large-scale sequencing of a mammary gland cDNA library, followed by nested PCR and 5-prime RACE, Kato et al. (2002) cloned SCYL1, which they called NTKL. The deduced 808-amino acid protein has a calculated molecular mass of 89.6 kD. Kato et al. (2002) also cloned 2 splice variants that harbor internal deletions and encode proteins of 791 and 707 amino acids, which they termed variant 1 and variant 2, respectively. NTKL has an N-terminal kinase-like domain and a C-terminal cluster of basic amino acids. NTKL shares 90% amino acid identity with mouse Ntkl, and like mouse Ntkl, it does not contain kinase subdomain 1. NTKL also shares sequence similarity with the S. cerevisiae Scy1 protein. Northern blot analysis detected a 2.8-kb transcript in all tissues tested.
In the mouse central nervous system (CNS), Schmidt et al. (2007) found that Scyl1 was prominently expressed in neuronal perikarya, cortical neurons, brainstem neurons, and anterior horn spinal cord neurons. The protein was also detected at synapses in the CNS, in the axons of peripheral nerves, and at neuromuscular junctions.
Using NTKL carrying 2 different epitope tags, Kato et al. (2002) found that NTKL forms multimers following transfection into COS-7 cells. They determined that NTKL forms a 300-kD trimer using crosslinking reagents. Biochemical analysis revealed no phosphorylation or autophosphorylation activity. Kato et al. (2002) found that the 707-amino acid NTKL variant, variant 2, localized to centrosomes during mitosis. During interphase, fluorescence-tagged variant 2 localized in the cytoplasm as well as centrosomes. However, at the beginning of mitosis, the fluorescence appeared as a pair of bright nuclear foci that followed centrosome localization throughout mitosis, while maintaining diffuse cytoplasmic labeling. Endogenous variant 2 in HeLa cells showed a similar staining pattern. Centrosomal localization was independent of microtubules.
Di et al. (2003) identified an Ntkl-binding protein (GORAB; 607983) in mouse that colocalized with Ntkl in cytoplasm and showed ubiquitous expression.
Kato et al. (2002) determined that the SCYL1 gene contains 18 exons and spans about 15 kb. Alternative splicing produces variant 1, which lacks half of exon 14, and variant 2, which lacks most of exon 14, all of exon 15, and half of exon 16.
By genomic sequence analysis, Liu et al. (2000) and Kato et al. (2002) mapped the SCYL1 gene to chromosome 11q13.
In 3 patients from 2 unrelated families with autosomal recessive spinocerebellar ataxia-21 (SCAR21; 616719) with hepatopathy, Schmidt et al. (2015) identified compound heterozygous truncating mutations in the SCYL1 gene (607982.0001-607982.0004). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Patient fibroblasts showed absence of the SCYL1 protein and massively enlarged Golgi apparatus.
In a 7-year-old girl with SCAR21, Spagnoli et al. (2019) identified a homozygous frameshift mutation in the SCYL1 gene (607982.0009). The mutation, which was found by exome sequencing, segregated with the disorder in the family and was not found in the gnomAD database. It was predicted to result in a loss of protein function. Studies of patient cells were not performed.
In 7 patients from 5 unrelated families with a phenotype overlapping SCAR21, Lenz et al. (2018) identified homozygous mutations in the SCYL1 gene (see, e.g., 607982.0005-607982.0008). There were 3 nonsense and 2 missense mutations, consistent with a loss of function. The patients, who were all under 12 years of age at the time of the report, were ascertained from a cohort of pediatric patients with unexplained cholestasis or acute liver failure who underwent whole-exome sequencing; the mutations were filtered against public databases. Available patient fibroblasts showed decreased SCYL1 protein compared to controls, and functional studies indicated impaired retrograde Golgi transport, suggesting a defect in intracellular trafficking. The patients did not have ataxia, but had other features that overlapped with SCAR21; Lenz et al. (2018) referred to this clinical variant as low gamma-glutamyltransferase (GGT) cholestasis, acute liver failure, and neurodegeneration syndrome (CALFAN; 616719).
Schmidt et al. (2007) found that the autosomal recessive mouse neurodegenerative disorder 'muscle deficient' (mdf) is caused by a homozygous 1-bp insertion (c.1169_1170insT) in exon 8 of the Scyl1 gene, resulting in a loss of function. Mdf mice show progressive neuromuscular atrophy, hindlimb paralysis, and phenotypes consistent with cerebellar involvement, such as gait ataxia, abnormal hindlimb posture, and tremor. Neuropathologic examination of mdf mice showed cerebellar atrophy, Purkinje cell loss, and optic nerve atrophy.
Pelletier et al. (2012) demonstrated that deletion of Scyl1 in mice caused an early-onset progressive motor neuron disease with features characteristic of amyotrophic lateral sclerosis (ALS; 105400). Mutant mice had growth retardation, waddling and abnormal gait, muscle wasting, and progressive motor dysfunction resulting in paralysis of the hind paws. Skeletal muscles of mutant mice showed neurogenic atrophy, fiber type switching, and disuse atrophy, and peripheral nerves showed axonal degeneration and segmental demyelination. There was also a reduction in the number of spinal ventral horn motor neurons, with swollen mitochondria in the remaining neurons and evidence of inflammation. However, there were no major cerebellar changes. Spinal cord ventral neurons from mutant mice showed redistribution of TDP43 (TARDBP; 605078) from the nucleus to cytoplasmic aggregates and the presence of ubiquilin-2 (UBQLN2; 300264) inclusions, as observed in ALS. Neuron-specific depletion, but not muscle-specific depletion, recapitulated the phenotypic changes observed in Slcy1-null mice, suggesting that Scyl1 acts in a neuron-autonomous manner to play a critical role in the survival of large motor neurons.
In 2 sibs, born of unrelated parents of European origin, with autosomal recessive spinocerebellar ataxia-21 (SCAR21; 616719) with hepatopathy, Schmidt et al. (2015) identified compound heterozygous mutations in the SCYL1 gene: a 1-bp deletion (c.937delG, NM_020680.3) in exon 7, resulting in a frameshift and premature termination (Val313CysfsTer6), and a 2-bp deletion (c.1509_1510delTG; 607982.0002) in exon 11, resulting in a frameshift and premature termination (Ala504ProfsTer15). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. Patient fibroblasts showed absence of the SCYL1 protein and massively enlarged Golgi apparatus.
For discussion of the 2-bp deletion (c.1509_1510delTG, NM_020680.3) in exon 11 of the SCYL1 gene, resulting in a frameshift and premature termination (Ala504ProfsTer15), that was found in 2 sibs with autosomal recessive spinocerebellar ataxia-21 (SCAR21; 616719) with hepatopathy by Schmidt et al. (2015), see 607982.0001.
In a 17-year-old girl of Cuban descent with autosomal recessive spinocerebellar ataxia-21 (SCAR21; 616719) with hepatopathy, Schmidt et al. (2015) identified compound heterozygous mutations in the SCYL1 gene: a G-to-A transition in intron 9 (c.1230+1G-A, NM_020680.3), resulting in the skipping of exon 9 and the loss of residues 373-410 of the HEAT domain, and a c.1636C-T transition (607982.0004) in exon 12, resulting in a gln546-to-ter (Q546X) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases.
For discussion of the c.1636C-T transition (c.1636C-T, NM_020680.3) in exon 12 of the SCYL1 gene, resulting in a gln546-to-ter (Q546X) substitution, that was found in a patient with autosomal recessive spinocerebellar ataxia-21 (SCAR21; 616719) with hepatopathy by Schmidt et al. (2015), see 607982.0003.
In a 3-year-old German boy (family 1) with low GGT cholestasis, acute liver failure, and neurodegeneration syndrome (CALFAN; 616719), Lenz et al. (2018) identified a homozygous c.1882C-T transition (c.1882C-T, NM_020680.3) in exon 14 of the SCYL1 gene, resulting in a gln628-to-ter (Q628X) substitution. The mutation was found by whole-exome sequencing and filtered against public databases. Patient fibroblasts showed decreased SCYL1 protein compared to controls, and functional studies indicated impaired retrograde Golgi transport.
In 2 sibs, born of consanguineous Pakistani parents (family 2), with low GGT cholestasis, acute liver failure, and neurodegeneration syndrome (CALFAN; 616719),
Lenz et al. (2018) identified a homozygous c.1433A-G transition in exon 11 of the SCYL1 gene, resulting in an asp478-to-gly (D478G) substitution at a highly conserved residue. The mutation was found by whole-exome sequencing and filtered against public databases. Patient fibroblasts showed decreased SCYL1 protein compared to controls, and functional studies indicated impaired retrograde Golgi transport.
In 2 sisters, born of consanguineous Turkish parents (family 4), with low GGT cholestasis, acute liver failure, and neurodegeneration syndrome (CALFAN; 616719), Lenz et al. (2018) identified a homozygous c.169C-T transition (c.169C-T, NM_020680.3) in exon 2 of the SCYL1 gene, resulting in a gln57-to-ter (Q57X) substitution. The mutation was found by whole-exome sequencing and filtered against public databases. Functional studies of the variant and studies of patient cells were not performed.
In a 5-year-old Italian boy (family 5) with low GGT cholestasis, acute liver failure, and neurodegeneration syndrome (CALFAN; 616719), Lenz et al. (2018) identified a homozygous c.314C-T transition (c.314C-T, NM_020680.3) in exon 3 of the SCYL1 gene, resulting in an ala105-to-val (A105V) substitution at a conserved residue in the protein kinase domain. The mutation was found by whole-exome sequencing and filtered against public databases. Patient fibroblasts showed decreased amounts of SCYL1 protein compared to controls; additional functional studies were not performed.
In a 7-year-old Italian girl with autosomal recessive spinocerebellar ataxia-21 (SCAR21; 616719), Spagnoli et al. (2019) identified a homozygous 1-bp duplication (c.1534dupT, NM_020680.3) in the SCYL1 gene, resulting in a frameshift and premature termination (Cys512LeufsTer8). The mutation, which was found by exome sequencing, segregated with the disorder in the family and was not found in the gnomAD database. It was predicted to result in a loss of protein function. Studies of patient cells were not performed.
Di, Y., Li, J., Fang, J., Xu, Z., He, X., Zhang, F., Ling, J., Li, X., Xu, D., Li, L., Li, Y.-Y., Huo, K. Cloning and characterization of a novel gene which encodes a protein interacting with the mitosis-associated kinase-like protein NTKL. J. Hum. Genet. 48: 315-321, 2003. [PubMed: 12783284] [Full Text: https://doi.org/10.1007/s10038-003-0031-5]
Kato, M., Yano, K., Morotomi-Yano, K., Saito, H., Miki, Y. Identification and characterization of the human protein kinase-like gene NTKL: mitosis-specific centrosomal localization of an alternatively spliced isoform. Genomics 79: 760-767, 2002. [PubMed: 12036289] [Full Text: https://doi.org/10.1006/geno.2002.6774]
Lenz, D., McClean, P., Kansu, A., Bonnen, P. E., Ranucci, G., Thiel, C., Straub, B. K., Harting, I., Alhaddad, B., Dimitrov, B., Kotzaeridou, U., Wenning, D., and 11 others. SCYL1 variants cause a syndrome with low gamma-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN). Genet. Med. 20: 1255-1265, 2018. [PubMed: 29419818] [Full Text: https://doi.org/10.1038/gim.2017.260]
Liu, S. C. H., Lane, W. S., Lienhard, G. E. Cloning and preliminary characterization of a 105 kDa protein with an N-terminal kinase-like domain. Biochim. Biophys. Acta 1517: 148-152, 2000. [PubMed: 11118629] [Full Text: https://doi.org/10.1016/s0167-4781(00)00234-7]
Pelletier, S., Gingras, S., Howell, S., Vogel, P., Ihle, J. N. An early onset progressive motor neuron disorder in Scyl1-deficient mice is associated with mislocalization of TDP-43. J. Neurosci. 32: 16560-16573, 2012. [PubMed: 23175812] [Full Text: https://doi.org/10.1523/JNEUROSCI.1787-12.2012]
Schmidt, W. M., Kraus, C., Hoger, H., Hochmeister, S., Oberndorfer, F., Branka, M., Bingemann, S., Lassmann, H., Muller, M., Macedo-Souza, L. I., Vainzof, M., Zatz, M., Reis, A., Bittner, R. E. Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration. EMBO Rep. 8: 691-697, 2007. [PubMed: 17571074] [Full Text: https://doi.org/10.1038/sj.embor.7401001]
Schmidt, W. M., Rutledge, S. L., Schule, R., Mayerhofer, B., Zuchner, S., Boltshauser, E., Bittner, R. E. Disruptive SCYL1 mutations underlie a syndrome characterized by recurrent episodes of liver failure, peripheral neuropathy, cerebellar atrophy, and ataxia. Am. J. Hum. Genet. 97: 855-861, 2015. [PubMed: 26581903] [Full Text: https://doi.org/10.1016/j.ajhg.2015.10.011]
Spagnoli, C., Frattini, D., Salerno, G. G., Fusco, C. On CALFAN syndrome: report of a patient with a novel variant in SCYL1 gene and recurrent respiratory failure. Genet. Med. 21: 1663-1664, 2019. [PubMed: 30531813] [Full Text: https://doi.org/10.1038/s41436-018-0389-6]