טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentMory Adi
SubjectDeciphering the Genetic Defect behind Kohlschutter-Tonz
Syndrome
DepartmentDepartment of Medicine
Supervisor Clinical Professor Ruth Gershoni-Baruch
Full Thesis textFull thesis text - English Version


Abstract

Kohlschutter-Tonz syndrome (KTZS) is an autosomal recessive neurodegenerative disorder, characterized by intellectual impairment, spasticity, epilepsy and amelogenesis imperfecta (AI). We investigated 16 new KTZS cases, from 7 families, all originating from one Druze village. Using Genome-Wide SNP arrays and polymorphic microsatellite markers, we have located a shared homozygote interval of 586,513bp on chromosomal region 16p13.3. The shared chromosomal region harbors 17 genes, Sanger sequencing analysis was undertaken for each gene's coding exons including exon-intron boundaries. Within the Drosophila rogdi homolog (ROGDI), a homozygous nonsense mutation c.469C>T, causing a premature stop codon, p.Arg157*, was identified. KTZS affected individuals were homozygote (n=15) for the nonsense mutation while healthy family members were either heterozygote or non carriers (n=20). We otherwise identified eight carriers out of 68 unrelated, healthy inhabitants of the village in question, screened for the mutation. The mutation was not present in 180 Druze individuals from various other Druze villages in northern Israel.

Human ROGDI encodes a leucin zipper protein of 287 amino acids, the function of which remains enigmatic. Large scale RNA expression studies show highest expression level of ROGDI in the nervous system compared to other organ systems. Our expression analyses indicate that human ROGDI is widely expressed, with higher levels in spinal cord, adult brain, heart, bone marrow, and peripheral blood, and lower but detectable levels in many other tissues including fetal brain. Quantitative RNA expression analyses were performed on RNA extracted from patients (n=12) and control's (n=6) blood samples. ROGDI's expression was markedly reduced in patients (80%-55%) compared to mean value obtained from controls, indicating nonsense-mediated mRNA decay. A nuclear localization of ROGDI was demonstrated by immunofluorescence studies, and strong labeling of the nuclear envelope was detected suggesting specific nuclear envelope localization for ROGDI.

This study provides the clinical data that best characterizes 16 KTZS patients. The unique KTZS phenotype that compiles mental and verbal deficiency, motor deterioration, seizures and AI is common to all affected individuals. However, age at onset and severity of convulsions parallel the progression of mental and motor disability and invariably vary among affected sibs. By late adolescence and early twenties KTZS individuals are bedridden, fed by gastrostomy, spastic, practically with no cognitive and language perception. These cases highlight a disease that is progressive by nature, the course of which is uniform, albeit being heterogeneous, as regards the severity of symptoms (seizures) and the rate of mental and motor regression.