Alternative titles; symbols
HGNC Approved Gene Symbol: DYNC2H1
SNOMEDCT: 726032008;
Cytogenetic location: 11q22.3 Genomic coordinates (GRCh38) : 11:103,109,426-103,479,863 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q22.3 | Short-rib thoracic dysplasia 3 with or without polydactyly | 613091 | Autosomal recessive; Digenic recessive | 3 |
The DYNC2H1 gene encodes a protein involved in ciliary intraflagellar transport (IFT), an evolutionarily conserved process that is essential for ciliogenesis and plays a role in cell signaling events. DYNC2H1 is the central ATPase subunit of the IFT dynein-2 complex, the principal minus-end directed microtubule motor that drives retrograde transport of the IFT-A protein complex that regulates tip-to-base transport in cilia. DYNC2H1 has a typical dynein heavy chain organization (summary by Schmidts et al., 2013).
Dyneins are a family of high molecular mass motor proteins that produce directed movement along microtubules. The dynein family is divided into 2 functional classes. The axonemal dyneins constitute the outer and inner arms on the doublet microtubules of ciliary and flagellar axonemes, where they generate the localized sliding motion between doublets that underlies the oscillatory beating of these organelles. Cytoplasmic dynein participates in numerous cellular activities. Both axonemal and cytoplasmic dyneins are multisubunit proteins containing 2 or 3 heavy chain polypeptide subunits of molecular mass greater than 500 kD, as well as 5 to 8 subunits of smaller size (summary by Gibbons et al., 1994). Within the dynein complex, the dynein heavy chain is the actual motor. The intermediate chains of both cytoplasmic and axonemal dynein appear to play a role in directing the dynein molecule to its appropriate subcellular target site. The light intermediate chains, with molecular masses of 55 to 59 kD, are unique to cytoplasmic dynein and contain consensus ATPase elements. Both axonemal and cytoplasmic dyneins also contain light chains of 8 to 25 kD (summary by Vaughan et al., 1996).
Gibbons et al. (1994) identified DYH1b, a sea urchin dynein heavy chain related to the principal cytoplasmic dynein heavy chain, DYH1a (see DNCL, 600112). Criswell et al. (1996) cloned cDNAs encoding DHC1b, the rat DYH1b homolog. Quantitative RT-PCR revealed that DHC1b is expressed in ciliated and nonciliated tissues. By immunofluorescence, the authors found that DHC1b is present in the cytoplasm of ciliated rat tracheal epithelial (RTE) cells, often accumulating at the apical ends of cells. However, the protein did not appear to be a component of RTE cilia. Criswell et al. (1996) suggested that DHC1b is a cytoplasmic dynein that may participate in intracellular trafficking in polarized cells. Criswell and Asai (1998) found that rat testis contains 3 DHC1b-like dynein heavy chains, one of which is the product of the DHC1b gene.
By RT-PCR with degenerate primers based on a conserved region of dynein heavy chains, Vaisberg et al. (1996) isolated cDNAs encoding DHC2. They considered DHC2 to be the human DYH1b homolog because the predicted partial protein sequences are 92% identical. DHC2 is a highly diverged member of the cytoplasmic dynein heavy chain family; it shares only 34% identity with DNCL. Using immunofluorescence, Vaisberg et al. (1996) localized DHC2 predominantly to the Golgi apparatus. The Golgi dispersed upon microinjection of antibodies against DHC2, suggesting that this motor is involved in establishing proper Golgi organization. Northern blot analysis demonstrated that DHC2 is expressed as an approximately 15-kb mRNA in various mammalian cell lines and human tissues, including those that make neither cilia nor flagella.
Dagoneau et al. (2009) stated that the human DYNC2H1 gene encodes a 4,314-amino acid protein.
Merrill et al. (2009) stated that the human DYNC2H1 gene contains 90 exons.
Crystal Structure
Schmidt et al. (2015) presented the crystal structure of the human cytoplasmic dynein-2 motor bound to the ATP-hydrolysis transition state analog ADP-vanadate. The structure revealed a closure of the motor's ring of 6 AAA+ domains (ATPases associated with various cellular activities: AAA1-AAA6). This induces a steric clash with the linker, the key element for the generation of movement, driving it into a conformation that is primed to produce force. Ring closure also changes the interface between the stalk and buttress coiled-coil extensions of the motor domain. This drives helix sliding in the stalk, which causes the microtubule binding domain at its tip to release from the microtubule. Schmidt et al. (2015) concluded that their structure elucidates how ATP hydrolysis leads to linker remodeling and microtubule affinity regulation.
By analysis of somatic cell and radiation hybrid panels, Kastury et al. (1997) mapped the DNCH2 gene to chromosome 11q13.5. By genomic sequence analysis, Pazour et al. (2006) mapped the DNCH2 gene to chromosome 11q21-q22.1.
Gross (2013) mapped the DYNC2H1 gene to chromosome 11q22.3 based on an alignment of the DYNC2H1 sequence (GenBank AB290167) with the genomic sequence (GRCh37).
Homozygous and compound heterozygous mutations in the DYNC2H1 gene have been identified in patients with short-rib thoracic dysplasia-3 with or without polydactyly (SRTD3; 613091). This disorder has been referred to as asphyxiating thoracic dysplasia-3 (ATD3), Jeune syndrome, and short-rib polydactyly types I (SRPS1), IIB (SRPS2B), and III (SRPS3).
Dagoneau et al. (2009) identified biallelic mutations in the DYNC2H1 gene (see, e.g., 603297.0001-603297.0006) in patients diagnosed
with asphyxiating thoracic dystrophy and in patients diagnosed with short rib-polydactyly type III. Their findings demonstrated that ATD and SRPS III belong to the same heterogeneous spectrum of conditions and are allelic disorders.
Using a combination of SNP mapping, exome sequencing, and Sanger sequencing, Schmidts et al. (2013) identified 34 DYNC2H1 mutations, only 2 of which had previously been identified, in 29 (41%) of 71 patients diagnosed with asphyxiating thoracic dystrophy from 19 (33%) of 57 families. Most of the mutations were private, occurring in only 1 family. The variants included 13 terminating mutations and 21 missense mutations distributed across the gene, with some clustering of the missense mutations in functional domains. All mutations occurred in homozygous or compound heterozygous state, and no patients had 2 truncating mutations, suggesting that the human phenotype is at least partly hypomorphic. Two patients carried 3 pathogenic mutations in the DYNC2H1 gene. No functional studies were performed. The phenotype was dominated by abnormal bone development, including short ribs, small thorax, brachydactyly, and shortened long bones. Polydactyly was not a feature; only 1 patient had unilateral polydactyly. Retinal, hepatic, renal, or pancreatic involvement was rare, having been observed in 1 or 2 patients overall. Patient fibroblasts showed defects in retrograde intraflagellar transport (IFT), as demonstrated by accumulation of anterograde proteins IFT57 (606621) and IFT88 (600595) in the ciliary tips. However, the extent of this cellular defect varied significantly among patients. Ciliary length and number were similar to controls. The patients were mainly of northern European or Turkish origin, and the findings indicated that DYNC2H1 mutations are the most frequent overall cause of ATD.
In affected members of a consanguineous family and in 2 isolated cases diagnosed with short rib-polydactyly syndrome type III, Merrill et al. (2009) identified homozygosity or compound heterozygosity for mutations in the DYNC2H1 gene. The abnormalities in short rib-polydactyly syndrome are primarily related to the effect on the skeleton, reflecting an essential role for DYNC2H1 in cilia function in cartilage.
In an individual with short rib-polydactyly syndrome type II from a nonconsanguineous German family, Thiel et al. (2011) identified heterozygosity for an insertion mutation in the NEK1 gene (604588.0003) and heterozygosity for a missense mutation in the DYNC2H1 gene (603297.0016); no second mutation was found in either gene, and each parent was heterozygous for one of the mutations.
El Hokayem et al. (2012) analyzed the DYNC2H1 gene in 8 unrelated cases of short rib-polydactyly syndrome type II, all of which were either terminated pregnancies or cases of neonatal death and were negative for mutation in the NEK1 gene, and identified compound heterozygosity for mutations in DYNC2H1 in 4 cases (see, e.g., 603297.0017-603297.0020).
Using exome sequencing, Badiner et al. (2017) identified 3 patients with a severe phenotype thought to be most consistent with short-rib polydactyly type I. All 3 patients were compound heterozygous for mutations in DYNC2H1; 5 of the mutations were missense changes at highly conserved residues, and 1 was a null mutation. All of the mutations were rare, including 4 that had not previously been reported in public sequence databases or in patients with short-rib polydactyly.
Ocbina et al. (2011) stated that null mutations in the Dync2h1 gene result in loss of Shh (600725)-dependent signaling in the embryonic mouse neural tube and death at around embryonic day 10.5. Immunohistochemical analysis revealed that Dync2h1 was enriched at the base of the cilium and in punctae along the axoneme of wildtype mouse embryonic fibroblasts (MEFs). In Dync2h1 -/- MEFs, cilia showed abnormal morphology and accumulation of hedgehog pathway proteins, suggesting a block in retrograde ciliary protein transport. Lowering the amount of the ciliary anterograde trafficking protein Ift172 (607386) to about 60% of wildtype levels partially rescued the Dync2h1 -/- phenotype, including ciliary morphology and hedgehog signaling, and extended embryo survival. Reduction in the ciliary retrograde trafficking protein Ift122 (606045) also suppressed the Dync2h1 -/- phenotype. Ocbina et al. (2011) concluded that Dync2h1 is required for normal cilia architecture and retrograde transport of proteins along cilia.
In a consanguineous Moroccan family with 2 children manifesting asphyxiating thoracic dystrophy (SRTD3; 613091), Dagoneau et al. (2009) identified homozygosity for 2 missense mutations in the DYNC2H1 gene: an A-to-T transversion at nucleotide 5971, resulting in a met-to-leu substitution at codon 1991 (M1991L), and an A-to-G transition at nucleotide 11284, resulting in a met-to-val substitution at codon 3762 (M3762V; 603297.0002). Carriers of either of these mutations in cis on only 1 allele were asymptomatic.
For discussion of the met3762-to-val (M3762V) mutation in the DYNC2H1 gene that was found in compound heterozygous state in patients with asphyxiating thoracic dystrophy (SRTD3; 613091) by Dagoneau et al. (2009), see 603297.0001.
In a nonconsanguineous French family with 2 fetuses clinically diagnosed with asphyxiating thoracic dystrophy (SRTD3; 613091), Dagoneau et al. (2009) identified compound heterozygosity for a frameshift mutation in exon 5 of the DYNC2H1 gene, an insertion of 29 nucleotides following position 654, and a missense mutation (603297.0004). The insertion mutation resulted in a glu-to-leu substitution at codon 219 followed by a frameshift with a termination codon 2 amino acids later (Glu219LeufsTer2).
In a nonconsanguineous French family with 2 fetuses clinically diagnosed with asphyxiating thoracic dystrophy (SRTD3; 613091), Dagoneau et al. (2009) identified an A-to-G transition at nucleotide 9044 in exon 57 of the DYNC2H1 gene resulting in an asp-to-gly substitution at codon 3015 (D3015G). A frameshift mutation was present on the other allele (603297.0003).
In affected members of 3 unrelated Dutch families (JATD-1, JATD-2, and JATD-6) with SRTD3, Schmidts et al. (2013) identified the D3015G mutation in compound heterozygous state with other mutations in the DYNC2H1 gene.
In a 19-year-old patient with a clinical diagnosis of asphyxiating thoracic dystrophy (SRTD3; 613091), who was the product of a nonconsanguineous French union, Dagoneau et al. (2009) identified compound heterozygosity for 2 mutations in the DYNC2H1 gene: a T-to-C transition at nucleotide 3719 in exon 25, resulting in an ile-to-thr substitution at codon 1240 (I1240T), and a G-to-T transversion at nucleotide 10063 in exon 66, resulting in a gly3355-to-ter (G3355X) substitution (603297.0006).
In a German girl (JATD-8) with SRTD3, Schmidts et al. (2013) identified the I1240T mutation in compound heterozygous state with another mutation in the DYNC2H1 gene.
For discussion of the gly3355-to-ter (G3355X) mutation in the DYNC2H1 gene that was found in compound heterozygous state in a patient with asphyxiating thoracic dystrophy (SRTD3; 613091) by Dagoneau et al. (2009), see 603297.0005.
In 4 affected offspring, born to first-cousin parents (family R01-314), who were clinically diagnosed with short rib-polydactyly syndrome type III (SRTD3; 613091), Merrill et al. (2009) detected homozygosity for a C-to-T transition at nucleotide 1759 in exon 12 of the DYNC2H1 gene, predicted to lead to the amino acid substitution arg587 to cys (R587C). The unaffected parents and sib were heterozygous for the mutation. The authors noted that this family showed phenotypic variability, since the female proband did not have polydactyly, whereas the 3 other sibs exhibited postaxial polydactyly of both hands and feet.
In a patient clinically diagnosed with short rib-polydactyly syndrome type III (SRTD3; 613091) from a nonconsanguineous family, Merrill et al. (2009) found a heterozygous 6614G-A transition in exon 41 of the DYNC2H1 gene that caused substitution of his for arg at codon 2205 (R2205H). The other DYNC2H1 allele carried a nonsense mutation (603297.0009).
In a patient clinically diagnosed with short rib-polydactyly syndrome type III (SRTD3; 613091) from a nonconsanguineous family, Merrill et al. (2009) found an 8512C-T transition in exon 53 of the DYNC2H1 gene that caused premature protein termination (R2838X), in compound heterozygosity with a missense mutation (603297.0008).
In a patient with a clinical diagnosis of short rib-polydactyly syndrome type III (SRTD3; 613091) from a nonconsanguineous family, Merrill et al. (2009) detected compound heterozygosity for mutations in the DYNC2H1 gene. One allele carried a change of 2 consecutive basepairs in exon 5 (624_625GT-AA). The first nucleotide change altered the last base of codon 208 without changing the encoded amino acid, and the second change predicted a phe209-to-ile (F209I) substitution. The other allele carried a splice donor site mutation (603297.0011).
In an individual with a clinical diagnosis of short rib-polydactyly syndrome type III (SRTD3; 613091), Merrill et al. (2009) found heterozygosity for alteration of the splice donor site of intron 33 of the DYNC2H1 gene (IVS33+1G-T). Reverse transcriptase and quantitative PCR indicated that the resulting transcript was subject to nonsense-mediated decay. The other allele carried substitution of 2 basepairs in exon 5 (603297.0010).
In a fetus with a clinical diagnosis of short rib-polydactyly syndrome type III (SRTD3; 613091) from a nonconsanguineous French family, Dagoneau et al. (2009) identified an A-to-G transition at nucleotide 4610 in exon 30 of the DYNC2H1 gene resulting in a gln-to-arg substitution at codon 1537 (Q1537R). This mutation was found in compound heterozygosity with another missense mutation (G2461V; 603297.0013).
In a fetus with a clinical diagnosis of short rib-polydactyly syndrome type III (SRTD3; 613091) from a nonconsanguineous French family, Dagoneau et al. (2009) identified a G-to-T transversion at nucleotide 7382 in exon 45 of the DYNC2H1 gene, resulting in a gly-to-val substitution at codon 2461 (G2461V). This mutation was found in compound heterozygosity with another missense mutation (Q1537R; 603297.0012).
In 3 fetuses with a clinical diagnosis of short rib-polydactyly syndrome type III (SRTD3; 613091), the offspring of a nonconsanguineous couple from Madagascar, Dagoneau et al. (2009) identified compound heterozygosity for mutations in the DYNC2H1 gene. The paternal allele carried a 5959A-G transition in exon 38, resulting in a thr1987-to-ala (T1987A) substitution, and the maternal allele carried a 1-bp deletion (10130delT; 603297.0015) in exon 67 that resulted in a frameshift and premature termination (Leu3377CysfsTer34).
For discussion of the 1-bp deletion in the DYNC2H1 gene (10130delT) that was found in compound heterozygous state in 3 fetuses with short rib-polydactyly syndrome type III (SRTD3; 613091) by Dagoneau et al. (2009), see 603297.0014.
In an individual with a clinical diagnosis of short rib-polydactyly syndrome type III (SRTD3; 613091) from a nonconsanguineous family of German origin, Thiel et al. (2011) identified a heterozygous 11747G-A transition in the DYNC2H1 gene, resulting in a gly3916-to-asp (G3916D) substitution; this individual was also heterozygous for a 1-bp insertion (1640insA) in the NEK1 gene (604588.0003). No second mutation was found in either gene, and each parent was heterozygous for one of the mutations, which were not found in 382 population-matched control chromosomes. Thus, biallelic digenic inheritance was indicated.
In a male fetus with a clinical diagnosis with short rib-polydactyly syndrome type III (SRTD3; 613091) from a pregnancy terminated at 15 weeks, El Hokayem et al. (2012) identified compound heterozygosity for 2 missense mutations in the DYNC2H1 gene: a 7985G-A transition in exon 49, resulting in an arg2662-to-gln (R2662Q) substitution, and a 7486C-T transition in exon 46, resulting in a pro2496-to-ser (P2496S; 603297.0018) substitution in the ATP binding and hydrolysis domain. The nonconsanguineous Vietnamese parents were each heterozygous for 1 of the mutations, neither of which was found in 200 control chromosomes.
For discussion of the pro2496-to-ser (P2496S) mutation in the DYNC2H1 gene that was found in compound heterozygous state in a fetus with short rib-polydactyly syndrome type III (SRTD3; 613091) by El Hokayem et al. (2012), see 603297.0017.
In a male fetus with a clinical diagnosis of short rib-polydactyly syndrome type III (SRTD3; 613091) from a pregnancy terminated at 15 weeks, El Hokayem et al. (2012) identified compound heterozygosity for a missense and a frameshift mutation in the DYNC2H1 gene: a 988C-T transition in exon 6, resulting in an arg330-to-cys (R330C) substitution in N-terminal region 1, and a 1-bp deletion (8534delA) in exon 53, causing a frameshift predicted to result in a premature termination codon (Asn2845IlefsTer8; 603297.0020). The nonconsanguineous Haitian parents were each heterozygous for 1 of the mutations, neither of which was found in 200 control chromosomes.
For discussion of the 1-bp deletion in the DYNC2H1 gene (8534delA) that was found in compound heterozygous state in a fetus with short rib-polydactyly syndrome type III (SRTD3; 613091) by El Hokayem et al. (2012), see 603297.0019.
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