טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentShalata Adel
SubjectMapping and Identifying - MOCS1, the Gene Responsible for
Molybdenum Cofactor Deficiency Type A (MoCoD), and
the Discovery of MOCS1 Processed
Pseudogene (MOCS1P1)
DepartmentDepartment of Medicine
Supervisors Professor Hanna Mandel
Ms. Nadine Cohen


Abstract

The Molybdenum cofactor deficiency (MoCoD) is an autosomal-recessive fatal disorder manifested shortly after birth with profound neurological abnormalities and severe seizures unresponsive to any therapy. MoCoD leads to the combined deficient activities of sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase. Here we describe the first mapping of MOCS1 gene, responsible for MoCoD Type A, and the identification of its processed pseudogene MOCS1P1

We started the mapping with two consanguineous affected Kindreds of Israeli-Arab origin, including five patients. Using the full genome scan with microsattelite markers, homozygosity mapping and linkage analysis, we demonstrated linkage of the MoCoD disease gene to an 8-cM region on chromosome 6p21.2-3 between the markers D6S1641 and D6S1672.

Recruiting two additional affected families, we demonstrated the feasibility of prenatal diagnosis and carrier detection using microsatellite markers.

The bicistronic MOCS1 gene, identefied by Jochen Reiss, that encodes MOCS1A and MOCS1B proteins was mapped to MoCoD locus. The MOCS1 gene was found to be homologous to two bacterial and two plant genes involved in the early steps of molybdenum cofactor biosynthesis. We found four novel mutations, two mutations in MOCS1A and two mutations in MOCS1B.

We identified the MOCS1 processed pseudogene, MOCS1P1, which was mapped to the same locus. We physically mapped both MOCS1 gene and MOCS1P1 pseudogene to the same P1 artificial chromosome and determined the full genomic sequence of both. We described also the direct misleading contribution of MOCS1P1 to mutation screening of MOCS1 gene in MoCoD type A patients and the specific method to overcome this obstacle.