Alternative titles; symbols
HGNC Approved Gene Symbol: DYNC2LI1
Cytogenetic location: 2p21 Genomic coordinates (GRCh38) : 2:43,774,039-43,828,347 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p21 | Short-rib thoracic dysplasia 15 with polydactyly | 617088 | Autosomal recessive | 3 |
Dyneins are large, multisubunit motor proteins that are involved in a wide variety of cellular processes. Cytoplasmic dyneins are involved in vesicle transport, formation and localization of the Golgi complex, mitotic spindle assembly and positioning, nuclear migration, and chromosome movement. DYNC2LI1 is a light intermediate chain of the cytoplasmic dynein-2 complex and interacts directly with the heavy chain, DHC2 (DYNC2H1; 603297) (Grissom et al., 2002).
By microsequencing a 33-kD protein that coimmunoprecipitated with Dhc2 from COS-7 cells, followed by database analysis, Grissom et al. (2002) identified human DYNC2LI1, which they called D2LIC. The predicted 351-amino acid human protein contains an N-terminal P-loop and a C-terminal coiled-coil region. The human protein shares homology with dynein-1 light intermediate chains from other species, particularly in the N terminus. D2LIC orthologs are present in mouse, worm, fly, and algae. Northern blot analysis detected a 1.6-kb D2LIC transcript in HeLa cells and COS-7 cells. Western blot analysis showed expression of a 39-kD protein in COS-7 cells. Western blot analysis of mouse tissues revealed highest expression of D2lic in testis, with lower levels in kidney, brain, lung, and liver, and no expression heart. Immunocytochemical analysis of COS-7 cells demonstrated expression of D2lic in Golgi apparatus and colocalization with Dhc2.
By database analysis, Mikami et al. (2002) identified rat Dync2li1, which they termed Lic3. Immunohistochemical analysis demonstrated expression of Dhc2 and Lic3 in neonatal and adult mouse brain, particularly in the ependymal layer lining the lateral ventricles. Dhc2 and Lic3 were also expressed in a punctate manner in connecting cilia of bovine retina and in primary cilia of rat kidney epithelial cells.
Using quantitative RT-PCR for transcriptional analysis in a series of 16-week fetal tissues, Taylor et al. (2015) observed that DYNC2LI1 was more highly expressed in bone than in other embryonic tissues such as brain, cartilage, heart, liver, lung, placenta, and thymus. Immunohistochemistry of human cartilage growth plate revealed DYNC2LI1 expression in the perichondrium, periosteum, and primary spongiosa of bone. In addition, immunohistochemistry of DYNC2H1 (603297) and WDR34 (613363) showed an overlapping expression pattern. Taylor et al. (2015) concluded that their findings supported a role for DYNC2LI1 and the dynein-2 complex in human skeletal development.
Kessler et al. (2015) analyzed expression levels of DYNC2LI1 in adult and fetal tissues and found the highest expression levels in chondrocytes, brain, and kidney. No differences between fetal and adult tissues were observed except for higher fetal expression in brain, kidney, and lungs. The authors noted that all 3 isoforms were expressed in the examined tissues, with highest contribution from the 2 longest isoforms. By immunofluorescence in ciliated fibroblasts, Kessler et al. (2015) confirmed localization of the DYNC2LI1 protein to the cytoplasm and centrosomes, as well as around the basal body and transition zone of the primary cilium.
Grissom et al. (2002) stated that the DYNC2LI1 gene maps to chromosome 2.
Gross (2016) mapped the DYNC2LI1 gene to chromosome 2p21 based on an alignment of the DYNC2LI1 sequence (GenBank AF151818) with the genomic sequence (GRCh38).
By immunoprecipitation analysis of COS-7 cells, Grissom et al. (2002) confirmed the association of D2lic with Dhc2. Based on its localization in Golgi, Grissom et al. (2002) proposed that D2LIC may play a role in maintaining Golgi organization by binding cytoplasmic dynein-2 to its Golgi-associated cargo.
Using immunologic and biochemical analyses, Mikami et al. (2002) showed that rat Lic3 associated with Dhc2. They presented evidence suggesting that dynein-2 is involved in generation and maintenance of cilia.
Perrone et al. (2003) confirmed association of the DHC2 and D2LIC orthologs in algae and found that the complex was involved with other intraflagellar transport (IFT) components in both algae and mammalian cells. Their studies suggested that the DHC2/D2LIC complex is the retrograde IFT motor and is conserved throughout ciliated organisms.
Taylor et al. (2015) performed RNAi against DYNC2LI1 in retinal epithelial (hTERT-RPE1) cells and observed significantly increased variation in cilia length, reproducing the phenotype observed in mutated fibroblasts (see 617083.0001). In addition, RNAi knockdown of DYNC2LI1 in RPE1 cells resulted in a 3-fold increase in the ratio of IFT88 (600595) retained in the primary cilium body relative to the proximal end. Taylor et al. (2015) concluded that DYNC2LI1 and the dynein-2 complex play an important role in regulation of primary cilia length, and that loss of DYNC2LI1 markedly impairs retrograde intraflagellar transport.
Kessler et al. (2015) analyzed fibroblasts after siRNA knockdown of DYNC2LI1 and observed no significant difference in percentage of ciliated cells compared to control fibroblasts. However, the mutant fibroblasts had significantly shorter cilia than controls, and significantly more cilia exhibited altered morphology, with broadened ciliary tips. In addition, the DYNC2LI1-depleted cells showed accumulation of the IFT components IFT57 (606621) and IFT88 in the bulbous ciliary tip, confirming a retrograde IFT defect in those cells.
In 3 fetuses from 3 unrelated families with short-rib thoracic dysplasia and polydactyly (SRTD15; 617088), Taylor et al. (2015) identified compound heterozygosity for missense, nonsense, and splice site mutations in the DYNC2LI1 gene (617083.0001-617083.0005) that segregated with disease. Fetal fibroblasts exhibited loss of cilia length regulation, ciliary accumulation of IFT components, and aberrant Hedgehog (see SHH, 600725) pathway activity, and the ciliary phenotype was rescued by wildtype DYNC2LI1.
In 1 of 3 sibs with SRTD and polydactyly, Kessler et al. (2015) identified compound heterozygosity for a nonsense (617083.0006) and a missense (617083.0007) mutation in the DYNC2LI1 gene; DNA was unavailable from the 2 other affected sibs.
In 6 patients from 3 families with SRTD, Niceta et al. (2018) identified compound heterozygosity for mutations in the DYNC2LI1 gene (617083.0007-617083.0011). Noting the wide clinical spectrum exhibited by the patients, including 1 who died shortly after birth and 1 who was in the fifth decade of life, the authors suggested that the severity of the phenotype might depend on the extent of defective DYNC2LI1 function.
In a 3-year-old girl with SRTD and congenital short gut, Bryson et al. (2021) identified compound heterozygosity for a previously reported missense mutation in the DYNC1LI1 gene (L117V; 617083.0001) and a frameshift mutation (617083.0012).
In 2 fetuses from unrelated families with short-rib thoracic dysplasia and polydactyly (SRTD15; 617088), Taylor et al. (2015) identified compound heterozygosity for mutations in the DYNC2LI1 gene. The first mutation was a c.349C-G transversion (rs201948500) in exon 6, resulting in a leu117-to-val (L117V) substitution at a conserved residue within an NTPase-related domain. In 1 fetus, the second mutation was a G-A transition in intron 12 (c.993+1G-A; 617083.0002), whereas in the other fetus, the second mutation was a c.372G-A transition in exon 6, resulting in a trp124-to-ter (W124X; 617083.0003) substitution. The unaffected parents in both families were each heterozygous for 1 of the mutations. Western blot analyses of fibroblast-derived lysates from both fetuses showed that DYNC2LI1 was markedly reduced, indicating that the mutations likely lead to loss of DYNC2LI1 stability. In addition, RT-PCR analysis of RNA derived from fibroblasts of the fetus with the splice site mutation demonstrated in-frame skipping of exon 12. Although the percentage of ciliated cells was only slightly reduced between fetal and control cells, Taylor et al. (2015) found that primary cilia length was highly variable in mutant fibroblasts compared to controls, with a substantial increase in the number of hyperelongated cilia up to 20 micrometers in length. Intraflagellar transport components IFT88 (600595), TRAF3IP1 (607380), and KIF3A (604683) all accumulated near the cilia tip in fetal fibroblasts, with 3- to 4-fold more IFT88 retained in the axonemes of mutant cilia compared to controls; this ratio, indicative of defective retrograde transport, was reduced by the expression of wildtype DYNC2LI1 in fetal fibroblasts. In addition, abnormal distribution of SMO (SMOH; 601500) into cilia of unstimulated mutant fibroblasts, as well as altered ratios of full-length to repressor GLI3 (165240), indicated impaired regulation of Hedgehog (see SHH, 600725) signaling in the fetuses.
In a 3-year-old girl who had SRTD with 4-limb postaxial polydactyly and congenital short gut, Bryson et al. (2021) identified compound heterozygosity for the L117V mutation in the DYNC1LI1 gene and a 2-bp deletion (c.18_19del; 617083.0012), causing a frameshift predicted to result in a premature termination codon (Trp7GlyfsTer6). Familial segregation was not reported.
For discussion of the c.993+1G-A transition in intron 12 of the DYNC2LI1 gene that was found in compound heterozygous state in a fetus with short-rib thoracic dysplasia and polydactyly (SRTD15; 617088) by Taylor et al. (2015), see 617083.0001.
For discussion of the c.372G-A transition in exon 6 of the DYNC2LI1 gene, resulting in a trp124-to-ter (W124X) substitution, that was found in compound heterozygous state in a fetus with short-rib thoracic dysplasia and polydactyly (SRTD15; 617088) by Taylor et al. (2015), see 617083.0001.
In a fetus with short-rib thoracic dysplasia and polydactyly (SRTD15; 617088), Taylor et al. (2015) identified compound heterozygosity for a c.1000G-T transversion in exon 13 of the DYNC2LI1 gene, resulting in a glu334-to-ter (E334X) substitution, and a c.993+3A-G transition in intron 12 (617083.0005). RT-PCR analysis of RNA derived from fetal fibroblasts demonstrated in-frame skipping of exon 12.
For discussion of the c.993+3A-G transition in intron 12 of the DYNC2LI1 gene that was found in compound heterozygous state in a fetus with short-rib thoracic dysplasia and polydactyly (SRTD15; 617088) by Taylor et al. (2015), see 617083.0004.
In a female patient with short-rib thoracic dysplasia and polydactyly (SRTD15; 617088), Kessler et al. (2015) identified compound heterozygosity for a c.622C-T transition (c.622C-T, NM_001193464) in exon 8 of the DYNC2LI1 gene, resulting in an arg208-to-ter (R208X) substitution, and a c.662C-T transition in exon 9, resulting in a thr221-to-ile (T221I; 617083.0007) substitution. The missense mutation was present in heterozygosity in the unaffected mother, brother, and son of the patient; DNA from her healthy father and 2 other affected sibs was unavailable. Both mutations occurred at highly conserved residues, and neither was present in 858 control chromosomes or in the ExAC database. The female patient lived to adulthood and had an unaffected son, whereas her affected older sister died 2 days after birth; their mother also had 3 miscarriages and 1 affected pregnancy was terminated at 19 weeks.
For discussion of the c.662C-T transition (c.662C-T, NM_001193464) in exon 9 of the DYNC2LI1 gene, resulting in a thr221-to-ile (T221I) substitution, that was found in compound heterozygous state in a patient with short-rib thoracic dysplasia and polydactyly (SRTD15; 617088) by Kessler et al. (2015), see 617083.0006.
In 5 affected individuals from 2 families with SRTD and polydactyly, Niceta et al. (2018) identified compound heterozygosity for the T221I mutation and another mutation in the DYNC2LI1 gene. In the 3 affected members of family 1, including the 2 Italian sisters (SC742D1 and SC741D1) originally reported by Digilio et al. (1997), now aged 42 years and 31 years, and a 4-year-old boy (BL1304-12) who was their second cousin once removed, the second mutation was a c.2T-C transition, resulting in a met1-to-? (M1?; 617083.0008) substitution. In the brother (MGM03-0553) and sister (MGM03-0552) of family 2, who were 23 and 16 years old, the second mutation was a 1-bp deletion (c.420delA; 617083.0009), causing a frameshift predicted to result in a val141-to-ter (V141X) substitution; their unaffected parents were each heterozygous for 1 of the mutations. The T221I variant was not found in the ExAC database, but the other variants were present at low frequencies, occurring as heterozygous changes in all instances.
For discussion of the c.2T-C transition (c.2T-C, NM_001193464.1) in the DYNC2LI1 gene, resulting in a met1-to-? (M1?) substitution, that was found in compound heterozygous state in 2 Italian sisters, who were originally reported by Digilio et al. (1997), and in their second cousin once removed with short-rib thoracic dysplasia with polydactyly (SRTD15; 617088) by Niceta et al. (2018), see 617083.0007.
For discussion of the 1-bp deletion (c.420delA, NM_001103464.1) in the DYNC2LI1 gene, resulting in a val141-to-ter (V141X) substitution, that was found in compound heterozygous state in 2 sibs with short-rib thoracic dysplasia with polydactyly (SRTD15; 617088) by Niceta et al. (2018), see 617083.0007.
In an infant girl who had short-rib thoracic dysplasia with polydactyly (SRTD15; 617088) and died within the first month of life, Niceta et al. (2018) identified compound heterozygosity for mutations in the DYNC2LI1 gene: a 1-bp insertion (c.123_124insA, NM_001193464.1), causing a frameshift predicted to result in a premature termination codon (Gly42ArgfsTer12), and a splice site mutation (c.658-11delT; 617083.0011) in intron 8. Her unaffected parents were each heterozygous for 1 of the mutations. Biologic material was not available from the proband, but analysis of maternal mRNA demonstrated loss of mRNA containing the splice site change.
For discussion of the 1-bp deletion (c.658-11delT, NM_001193464.1) in intron 8 of the DYNC2LI1 gene, predicted to disrupt normal splicing, that was found in compound heterozygous state in an infant girl with short-rib thoracic dysplasia with polydactyly (SRTD15; 617088) by Niceta et al. (2018), see 617083.0010.
For discussion of the 2-bp deletion (c.18_19del) in the DYNC2LI1 gene, causing a frameshift predicted to result in a premature termination codon (Trp7GlyfsTer6), that was found in compound heterozygous state in a 3-year-old girl with short-rib thoracic dysplasia with polydactyly and congenital short gut (SRTD15; 617088) by Bryson et al. (2021), see 617083.0001.
Bryson, L. J., Flynn, D. M., Sabharwal, A., Ahmed, S. F., Kinning, E. A child with congenital short gut associated with DYNC2LI1 ciliopathy. Clin. Dysmorph. 30: 66-68, 2021. [PubMed: 32815859] [Full Text: https://doi.org/10.1097/MCD.0000000000000341]
Digilio, M. C., Marino, B., Giannotti, A., Dallapiccola, B. Atrioventricular canal defect and postaxial polydactyly indicating phenotypic overlap of Ellis-van Creveld and Kaufman-McKusick syndromes. (Letter) Pediat. Cardiol. 18: 74-75, 1997. [PubMed: 8960501] [Full Text: https://doi.org/10.1007/s002469900116]
Grissom, P. M., Vaisberg, E. A., McIntosh, J. R. Identification of a novel light intermediate chain (D2LIC) for mammalian cytoplasmic dynein 2. Molec. Biol. Cell 13: 817-829, 2002. [PubMed: 11907264] [Full Text: https://doi.org/10.1091/mbc.01-08-0402]
Gross, M. B. Personal Communication. Baltimore, Md. 8/18/2016.
Kessler, K., Wunderlich, I., Uebe, S., Falk, N. S., Giessl, A., Brandstatter, J. H., Popp, B., Klinger, P., Ekici, A. B., Sticht, H., Door, H.-G., Reis, A., Roepman, R., Seemanova, E., Thiel, C. T. DYNC2LI1 mutations broaden the clinical spectrum of dynein-2 defects. Sci. Rep. 5: 11649, 2015. Note: Electronic Article. [PubMed: 26130459] [Full Text: https://doi.org/10.1038/srep11649]
Mikami, A., Tynan, S. H., Hama, T., Luby-Phelps, K., Saito, T., Crandall, J. E., Besharse, J. C., Vallee, R. B. Molecular structure of cytoplasmic dynein 2 and its distribution in neuronal and ciliated cells. J. Cell Sci. 115: 4801-4808, 2002. [PubMed: 12432068] [Full Text: https://doi.org/10.1242/jcs.00168]
Niceta, M., Margiotti, K., Digilio, M. C., Guida, V., Bruselles, A., Pizzi, S., Ferraris, A., Memo, L., Laforgia, N., Dentici, M. L., Consoli, F., Torrente, I., Ruiz-Perez, V. L., Dallapiccola, B., Marino, B., De Luca, A., Tartaglia, M. Biallelic mutations in DYNC2LI1 are a rare cause of Ellis-van Creveld syndrome. Clin. Genet. 93: 632-639, 2018. [PubMed: 28857138] [Full Text: https://doi.org/10.1111/cge.13128]
Perrone, C. A., Tritschler, D., Taulman, P., Bower, R., Yoder, B. K., Porter, M. E. A novel dynein light intermediate chain colocalizes with the retrograde motor for intraflagellar transport at sites of axoneme assembly in Chlamydomonas and mammalian cells. Molec. Biol. Cell 14: 2041-2056, 2003. [PubMed: 12802074] [Full Text: https://doi.org/10.1091/mbc.e02-10-0682]
Taylor, S. P., Dantas, T. J., Duran, I., Wu, S., Lachman, R. S., University of Washington Center for Mendelian Genomics Consortium, Nelson, S. F., Cohn, D. H., Vallee, R. B., Krakow, D. Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome. Nature Commun. 6: 7092, 2015. Note: Electronic Article. [PubMed: 26077881] [Full Text: https://doi.org/10.1038/ncomms8092]