Disease relevance of HMCN1

• Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family [1].
• Posterior column ataxia with retinitis pigmentosa (AXPC1) maps to chromosome 1q31-q32 [2].
• GAA-deficient (AMD) Japanese quails exhibit progressive myopathy and cannot lift their wings, fly, or right themselves from the supine position (flip test) [3].
• The randomization between vincristine (VCR) plus dactinomycin (AMD) and the same two drugs plus doxorubicin (ADR) had a minimal effect on RT toxicity [4].
• PURPOSE: To evaluate the effect of the sequential addition of doxorubicin (DOX) and cyclophosphamide (CTX) to the combination of vincristine (VCR) and dactinomycin (AMD) on the relapse-free survival of children with clear-cell sarcoma of the kidney (CCSK) [5].

Psychiatry related information on HMCN1

• Significant differences (t=-2.91, df=25, p=0.008) were found between the Alzheimer's Disease Assessment Scale (ADAS) total scores in the ARMD patients with at least one epsilon 4 allele (mean=24.2) compared with the ARMD patients without the epsilon 4 allele (mean=14.7) [6].
• Thus, with a view to determining whether APOE genotyping could be useful in the early detection of AD, we determined the Apoe allele frequencies in patients with memory complaints without dementia (age-related memory decline, ARMD) [6].
• METHODS: Four groups were used in this psychometric evaluation: an asymptomatic normative population (NP; n = 50), an acute musculoskeletal disorder population (AMD; n = 52), a chronic disabled musculoskeletal disorder population (CDMD; n = 230), and a heterogeneous pain population (HP; n = 114) [7].

High impact information on HMCN1

• Age-related macular degeneration (AMD; OMIM #603075) is the most frequent cause of visual impairment in the elderly population, with severe disease affecting nearly 10% of individuals of European descent over the age of 75 years [8].
• Detailed analysis showed a common haplotype associated with decreased risk of AMD that was present on 20% of chromosomes of controls and 8% of chromosomes of individuals with AMD [8].
• Mutations were not observed in any of the 11 exons of EFEMP1 nor in exon 104 of hemicentin-1 [9].
• A recently identified Gln5345Arg change in HEMICENTIN-1 on chromosome 1q25 was not detected in 274 affected members in the restricted group with AMD, 346 additional patients with AMD, and 237 unaffected controls [10].
• Here, we narrow the ARMD1 locus to 14.9 Mb between LAMB2 and D1S3469, a region containing 50 known genes [1].

Chemical compound and disease context of HMCN1

• Elderly human subjects with and without AMD can safely take supplements of lutein up to 10 mg/d for 6 months with no apparent toxicity or side effects [11].
• RESULTS: In the 291 eyes analyzed, NIR fluorescence was observed in 51 and was graded weak in 27 with wet age-related macular degeneration (AMD, 10 cases), dry AMD with pigment clumping (n=7), chronic central serous choroidopathy (CSC; n=5), choroidal nevi (n=2), subretinal hemorrhages (n=2), and chloroquine maculopathy (n=1) [12].
• Experiments using 32P-labeled DNA fragments obtained from a human gene showed that ultraviolet A-irradiated folic acid or PCA caused DNA cleavage specifically at consecutive G residues in double-stranded DNA after Escherichia coli formamidopyrimidine-DNA glycosylase or piperidine treatment [13].
• The effect of dimethylsulfoxide (DMSO) and iododeoxyuridine (IUdR) on the growth characteristics of two established human glioblastoma cell lines (FG and HMCN-1) was studied [14].
• The night blindness associated with Sorsby fundus dystrophy can be reversed over the short term with vitamin A. A significant trend for decreased risk for advanced or exudative ARMD has been reported among those whose diets contain a higher content of carotenoids, such as spinach and collard greens [15].

Biological context of HMCN1

• It was also identified in 11 other individuals, all of whom share a haplotype, which envelops HEMICENTIN-1, with the large AMD family [1].
• Two exons of the CFH gene and four exons of the Hemicentin-1 gene were amplified by polymerase chain reaction and sequenced directly [16].
• RESULTS: After direct sequencing, a point mutation in exon 29 was found in one of the 25 dry AMD patients [17].
• We tested for mutations in linked families and examined SNPs in two candidate genes, hemicentin-1 and EFEMP1, in subsamples (145 and 189 sib pairs, respectively) of the data [9].
• We found an APOE epsilon 4 allele frequency of 0.315 in the ARMD group, similar to 0.293 in the AD group, in contrast to 0.057 in the control group [6].

Anatomical context of HMCN1

• Secreted from skeletal muscle and gonadal leader cells, hemicentin assembles into fine tracks at specific sites, where it contracts broad regions of cell contact into oriented linear junctions [18].
• Hemicentin tracks facilitate mechanosensory neuron anchorage to the epidermis, gliding of the developing gonad along epithelial basement membranes and germline cellularization [18].
• We have recently demonstrated that the precursor for pyocyanin, phenazine-1-carboxylic acid (PCA), increases oxidant formation and alters gene expression in human airway epithelial cells [19].
• Tau-2 IR was faint and did not change with age but was mildly increased in the retinal pigment epithelium (RPE) of eyes with RP and in the retina of eyes with ARMD [20].
• CONCLUSIONS: A relative lack of MP is associated with adiposity in men, and may underlie the association between body fat and risk for AMD progression in males [21].

Associations of HMCN1 with chemical compounds

• The amino acid at position 5345 of HEMICENTIN-1 was conserved as glutamine in eight species analyzed [1].
• METHODS: Twenty-five Japanese unrelated patients with dry AMD who were diagnosed by fluorescein angiography and indocyanine green angiography were chosen as the dry AMD group [17].
• CONCLUSION: We conclude that the addition of DOX to the combination of VCR plus AMD appeared to improve the 6-year relapse-free survival rate of children with CCSK [5].
• These results were achieved with the use of standard treatments, ie, surgery, RT, and chemotherapy using dactinomycin (AMD), vincristine (VCR), and Adriamycin [( ADR] doxorubicin; Adria Laboratories, Columbus, OH) [22].
• Consistent with these findings, we show that pharmacologic elevation of cAMP with the phosphodiesterase inhibitor Rolipram suppresses tumor cell growth in vitro and, upon oral administration, inhibits intracranial growth in xenograft models of malignant brain tumors with comparable efficacy to AMD 3465 [23].
• Associations between rs743137 (P = 0.05) and rs680638 (P = 0.022) in HMCN1 with calculated creatinine clearance progression were also observed [24].

Other interactions of HMCN1

• Exclusive segregation of Gln5345Arg with the disease haplotype in this large family, amino acid conservation of glutamine at this position among mammals, the non-conservative nature of the substitution and similarities to EFEMP1 support the conclusion that HEMICENTIN-1 is the ARMD1 gene [1].
• Polymorphisms in Complement Factor H and Hemicentin-1 Genes in a Japanese Population With Dry-type Age-related Macular Degeneration [16].
• CONCLUSION: In this study we found no relationship between allelic variation in the ABCR gene and the prevalence of dry AMD in Japanese unrelated patients [17].
• PURPOSE: To explore whether the mutation in the retina-specific ATP-binding cassette transporter (ABCR) gene, the Stargardt's disease gene, contributes to the prevalence of the dry form of age-related macular degeneration (dry AMD) in Japanese unrelated patients [17].
• Radiation hybrid mapping shows that the gene for OPTC is located on chromosome 1q31, close to the inherited eye diseases ARMD1 and AXPC1 [25].

Analytical, diagnostic and therapeutic context of HMCN1

• RT-PCR analysis demonstrated that exon 104 of HEMICENTIN-1 is alternatively spliced in various cell types [1].
• When a mutation was detected, the occurrence of a mutation was compared between these AMD patients and the control group [17].
• Antioxidant intervention studies indicated both similarities and differences between PCA and pyocyanin [19].
• The presence of some similar changes in human AMD retinas suggests that these findings are of broad significance for determining the likely events in transplantation of neurons in the human retina and elsewhere [26].
• METHODS: AF [787] fundus images (excitation [Exc.] 787 nm; emission [Emi.] >800 nm) were recorded with a confocal scanning laser ophthalmoscope, in 85 normal subjects (ages: 11-77 years) and in 25 patients with AMD and other retinal diseases [27].

References