Identification of mutations in Iranian patients DAX-1 gene with X-linked adrenal hypoplasia congenital

Objective [s]: X-linked adrenal hypoplasia congenital [X-linked AHC] is a rare disorder, characterized by infantile-onset acute primary adrenal insufficiency and hypogonadotropic hypogonadism [HH] at an average age of three weeks and onset in roughly 40% is in childhood. Its cause is an inactivating mutation in the [nuclear receptor subfamily 0, group B, member 1] NROB1 gene, DSS [dosage sensitive sex]-AHC vital region on the X-gene 1

Subjects and methods: In the present study, the [dosage-sensitive, sex reversal, adrenal hypoplasia congenital, important region on the X-chromosome, gene 1] DAX-1 gene from four Iranian patients with X-linked AHC was analyzed by means of polymerase chain reaction [PCR] and direct sequencing

Results: We identified a polymorphism [Rs6150] which encodes a cysteine [Cys] at position 38, a de novo deletion, c.849-928de79 bp, c.849-856ins, [TGCTGCA] mutation and a missense mutation, Leu262Gln, which encodes a leucine [Leu] for glutamine [Gin] at position 262

Conclusion: Both mentioned mutations are located at crucial and functional region DAX1 protein

They are detected in the C-terminal region of DAX1 protein which is involved by the conserved amino acid chain as well as transcriptional silencing domain. By considering other investigation, mutations in this region probably lead to produce a misfolded protein. Consequently, the misfolded protein would not work influentially in order to inhibit some gene expression

As a result, our findings will expand the variety of DAX1 mutations. On the other hand, it is revealed that these mutations play a key role in the pathogenesis of AHC, thus, recognizing these new mutations will facilitate the patients prognosis producer as well as raising the clinical knowledge about this rare disease

Identification of Xq22.1-23 as a region linked with hereditary recurrent spontaneous abortion in a family

Recurrent spontaneous abortion [RSA] is one of the most common health complications with a strong genetic component. Several genetic disorders were identified as etiological factors of hereditary X linked RSA. However, more genetic factors remain to be identified. In this study we performed linkage analysis on a large X linked RSA pedigree to find a novel susceptibility locus for RSA. A linkage scan using 11 microsatellites was performed in 27 members of a large pedigree of hereditary X-linked RSA. Two point parametric Linkage was performed using Superlink v 1.6 program. Evidence of linkage was observed to markers at Xq23, DXS7133 and at Xq22.1 DXS101, with LOD score of 3.12 and 1.60, respectively. Identified locus in this study may carry a responsible gene in RSA. Narrowing down of this region may leads to identification of this gene

role of tumor protein 53 mutations in common human cancers and targeting the murine double minute 2-P53 interaction for cancer therapy

The gene TP53 [also known as protein 53 or tumor protein 53], encoding transcription factor P53, is mutated or deleted in half of human cancers, demonstrating the crucial role of P53 in tumor suppression. There are reports of nearly 250 independent germ line TP53 mutations in over 100 publications. The P53 protein has the structure of a transcription factor and, is made up of several domains. The main function of P53 is to organize cell defense against cancerous transformation. P53 is a potent transcription factor that is activated in response to diverse stresses, leading to the induction of cell cycle arrest, apoptosis or senescence. The P53 tumor suppressor is negatively regulated in cells by the murine double minute 2 [MDM2] protein. Murine double minute 2 favors its nuclear export, and stimulates its degradation. Inhibitors of the P53- MDM2 interaction might be attractive new anticancer agents that could be used to activate wild-type P53 in tumors. Down regulation of MDM2 using an small interfering RNA [siRNA] approach has recently provided evidence for a new role of MDM2 in the P53 response, by modulating the inhibition of the cyclin-dependent kinase 2 [cdk2] by P21/WAF1 [also known as cyclin-dependent kinase inhibitor 1 or CDKinteracting protein 1]