Disease relevance of DIAPH1

• The gene responsible for autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive hearing loss in a large Costa Rican kindred was previously localized to chromosome 5q31 and named DFNA1 [1].
• Moreover, overexpression of p300 resulted in an increase in the level of DRF1 complex. p300 fused to the DNA binding domain of the E2 protein of papilloma virus stimulated E2-dependent reporter activity in response to RA or E1A in F9 cells [2].
• Eighteen patients with low-frequency hearing loss ( LFHL ), 10 males and 8 females with an average age of 27 years, were examined in order to classify their hearing loss, i.e. to find the topical site of the hearing lesion and to evaluate the aetiology of the hearing disorder [3].

High impact information on DIAPH1

part of a positive feedback loop amplifying signals through rho-ROCK via activation of LARG [4]

essential for myosin function and feedback activation of RhoA through LARG in neutrophil motility and polarity [5]

• Hpo, Sav, and Wts interact physically and functionally, and regulate DIAP1 levels, likely by Hpo-mediated phosphorylation and subsequent degradation [6].
• RhoD regulates endosome dynamics through Diaphanous-related Formin and Src tyrosine kinase [7].
• Since the Drf1 gene is either absent or not yet identified in the genome of model organisms such as yeast and Drosophila, these findings introduce a new level of complexity in the regulation of DNA replication of the human genome [8].
• We also found factors, designated DRF1 and DRF2, that bound specifically to a sequence element that is necessary and sufficient for RA- and E1A-mediated up-regulation of the c-jun gene [2].
• Previously we have shown that Diaphanous-related formin dDia2 is involved in the formation of filopodia [9].

Biological context of DIAPH1

• None of the hitherto-known DFNA loci, which has phenotypes bearing some resemblance to MD, had haplotypes in common with this large family affected by MD [10].
• A second human Dbf4/ASK-related protein, Drf1/ASKL1, is required for efficient progression of S and M phases [11].
• Moreover, we found that the KRE-M9 binding protein could serve as a differentiation repressing factor 1 (DRF-1) as shown by the decrease in levels of this protein with differentiation [12].
• Investigating a large German pedigree with non-syndromic hearing impairment of early onset and autosomal dominant mode of inheritance, linkage to known DFNA loci was excluded and in a subsequent genomic scan the phenotype was mapped to a 10-cM interval on chromosome 3q22; a maximum two-point lod score of 3.77 was obtained for the marker D3S1292 [13].
• After exclusion of the known DFNA loci with markers from the Hereditary Hearing Loss Homepage (URL: http://dnalab-www.uia.ac.be/dnalab/hhh), a genome wide scan was carried out using 358 highly informative microsatellite markers [14].

Anatomical context of DIAPH1

• The Diaphanous-related formin, Dia1, is recruited to endosomes by activated RhoB [15].
• The diaphanous-related formin homology 2 domain containing protein 1 (FHOD1) interacts with the Rac GTPase and activates the Rho-ROCK cascade leading to the formation of actin stress fibers [16].
• OBJECTIVE: To further characterize the phenotype of DFNA1 with comprehensive audiovestibular evaluation and computed tomography of the temporal bone [17].

Regulatory relationships of DIAPH1

• Dia1 localizes to and controls cadherin-mediated junctions in a RhoA-dependent manner [18].

Other interactions of DIAPH1

• By the candidate gene approach, mutation screening of the DIAPH1 and POU4F3 genes at 5q31 was performed [19].
• Only two NSHHI loci, DFNA1 and DFNA6/14/38, are associated with predominantly low-frequency loss [20].
• Candidate genes including COL4A5, DIAPH, and POU3F4 were excluded by clinical and molecular analyses [21].

Analytical, diagnostic and therapeutic context of DIAPH1

• RESULTS: During spirometry, the diaphragm inspiratory amplitude (DIA) increased from 1.34 +/- 0.18 cm to 1.80 +/- 0.18 cm (P = 0.007), whereas the diaphragmatic inspiratory (T1 diaph) increased from 1.27 +/- 0.15 to 1.53 +/- 0.23 sec, (P = 0.015, without change in diaphragmatic total time interval (Ttot diaph) [22].

References