Disease relevance of DYNC1H1

• Here we extend these analyses to investigate the DYNC1H1 genomic locus to determine if it is associated with sporadic amyotrophic lateral sclerosis (ALS) in a northern European-derived population [1].
• Cytogenetic analysis of the LB-831 cell line revealed a nearly triploid highly abnormal karyotype with numerous clonal chromosomal abnormalities involving chromosomes 1, 3, 5, 7, 13, and 15; several structurally abnormal marker chromosomes; and a putative homogeneously staining region on chromosome 7p at band p22 [2].
• All five melanomas evidencing t(1;6) involved band regions 6q11-13, while two different regions of chromosome 1 (p22, q12-q21) were shown to be translocated to 6q [3].
• The most common gains in anaplastic carcinoma were in chromosomes 7p (p22-pter, 31%), 8q (q22-qter, 23%), and 9q (q34-qter, 23%) [4].
• The putative nucleocapsid (p22) and envelope (gp35 and gp58) proteins have been expressed in cells by different vectors under various foreign promoters [5].

Psychiatry related information on DYNC1H1

• We have found no chromosome rearrangement detectable with the methods used and no correlation between fra(X) (p22) and the Rett syndrome [6].

High impact information on DYNC1H1

• We have cloned and expressed DNA fragments that encode the putative ATP-hydrolytic sites of the cytoplasmic dynein heavy chain from HeLa cells and from Dictyostelium [7].
• A polyclonal antiserum prepared against the dynein heavy chains has been used to isolate dynein heavy chain (DYHC) cDNAs from a trout testis lambda gt11 cDNA expression library. beta-galactosidase fusion proteins produced in lambda gt11 by these trout cDNAs cross-reacted with a heterologous anti-sea urchin dynein antiserum [8].
• All the DYHC cDNAs encode portions of a highly unusual DNA coding sequence comprised of 21 bp direct repeats [8].
• The peptide sequences derived from the p22 subunit indicated that this subunit is identical to Cdm1, previously identified as a multicopy suppressor of the temperature-sensitive cdc1-P13 mutant, whereas peptide sequences derived from the p42 subunit were identical to a previously uncharacterized ORF located on S. pombe chromosome 1 [9].
• It is suggested that LisH motifs contribute to the regulation of microtubule dynamics, either by mediating dimerization, or else by binding cytoplasmic dynein heavy chain or microtubules directly [10].

Biological context of DYNC1H1

• In addition we investigated patterns of diversity at DYNC1H1 in Japanese and Cameroonian populations to establish the evolutionary history for this gene and observed reduced genetic diversity in the northern Europeans suggestive of selection at this locus [1].
• In a dlc1-null mutant, Dhc1-dependent nuclear movement in meiotic prophase became irregular in its duration and direction [11].
• P19 and p22 were both DNA-cellulose binding proteins whose phosphorylation was altered by 1,25-(OH)2D3 treatment [12].
• The antisera were assayed using bacterially expressed proteins with amino acid sequences taken from the human cytoplasmic dynein heavy chain [13].
• METHODS: We recruited 226 CVD patients (atherothrombotic infarction, lacunar infarction, and transient ischemic attack) and 301 control subjects and analyzed C242T polymorphism of p22 PHOX by detection of restriction fragment length polymorphism [14].

Anatomical context of DYNC1H1

• To determine whether cytoplasmic dynein is expressed in melanocytes, we performed reverse transcriptase polymerase chain reaction using melanocyte cDNA and primers complementary to human brain cytoplasmic dynein heavy chain [15].
• We have previously shown that mutations in the cytoplasmic dynein 1 heavy chain 1 gene (Dync1h1) are causal in a mouse model of late-onset motor neuron degeneration but have found no association of the homologous sites in human DYNC1H1 with human motor neuron disease [1].
• The gp91 and p22 decreased during culture of monocytes, although the decrease was only apparent by 7 days in culture [16].
• However, as has been reported for THP-1 myelomonocytic cells, neither alveolar macrophages nor blood monocytes contain directly quantifiable levels of functional ICE forms (p22/p20 and p10) when assayed by immunoblots or by a sensitive capture ELISA that uses an irreversible, biotinylated ICE inhibitor [17].
• Recently, an association between the C242T polymorphism of p22 PHOX, an essential component of NADPH oxidase, and coronary artery disease (CAD) has been reported in several studies [14].

Associations of DYNC1H1 with chemical compounds

• Worms depleted for LIS1 pathway components (NUD-1, NUD-2, DHC-1, CDK-5, and CDKA-1) exhibited significant convulsions following PTZ and RNAi treatment [18].
• This new more active ICE form serves both as an intermediate enzyme to cleave p45 as well as a substrate for the formation of the final active ICE (ED50 of 1 nM L-742,395 labeling of p20 and for p22, an NH2-terminally extended form of p20) [19].
• In comparison, cimetidine had an IC50 value of 1.5 mM using microsomes from liver HL3 [20].
• The oxidation of metoprolol by human liver microsomes was impaired by histamine (IC50 values for ODM appearance at 25 microM: liver HL1 greater than 10, HL3 = 3.8 and HL4 = 3.7 mM) [20].
• [NEt4]2[Tc(CO)3Cl3] reacts with thiosemicarbazones derived from 2,2'-dipyridyl ketone (HL3) and 4-acetylpyridine (HL4) to form stable technetium(I) complexes of the compositions [Tc(CO)3Cl(HL3-Npy,Npy)] and [Tc2(CO)6Cl2(micro-HL4-Npy,S)] [21].

Physical interactions of DYNC1H1

• By this assay, the C-terminal part of the cytoplasmic dynein heavy chain 1 was identified as a putative interacting polypeptide of Dnali1 [22].

Other interactions of DYNC1H1

• Chromosomal localization of the human cytoplasmic dynein heavy chain gene DNCH2 to 11q21-->q22.1 [23].
• We have immunolocalised conventional cytoplasmic dynein heavy chain to the Golgi apparatus in cultured vertebrate cells [24].
• We also report that the overexpression of p50/dynamitin results in the loss of cytoplasmic dynein heavy chain from the membrane of peripheral Golgi elements [24].

Analytical, diagnostic and therapeutic context of DYNC1H1

• Localization of the human cytoplasmic dynein heavy chain (DNECL) to 14qter by fluorescence in situ hybridization [25].
• No association of DYNC1H1 with sporadic ALS in a case-control study of a northern European derived population: a tagging SNP approach [1].
• The identity of the other two subunits, p42 and p22, was determined following proteolytic digestion and sequence analysis of the resulting peptides [9].
• Immunoblotting was also used to detect p22 and p34 in lysates of the conjunctivae of infected guinea pigs [26].
• 22,000 (p22), 27,000 (p27) and 68,000 (p68), were separated by preparative SDS-PAGE [27].

References