The pedigrees of KTS patients suggest autosomal recessive inheritance. Although several mutations in the ROGDI gene have been linked to the cause of KTS, the connection between the enamel defect and the altered brain function of patients has not yet been found. ROGDI Rogdi protein homo12mer, Human The ROGDI gene is located on chromosome 16 and contains 11 exons. The ROGDI protein contains 287 amino acids and has a leucine zipper form. The function of this protein is not currently known. Expression studies have shown that the gene has high expression in the hippocampus. It is also highly expressed in other parts of the adult brain, spinal cord, peripheral blood, heart, and bone marrow. These studies showed low level of expression in the fetal brain which is consistent with the onset of symptoms occurring no earlier than one month after birth. Protein staining has provided evidence supporting that the ROGDI protein may be a part of the nuclear envelope. Studies also suggest that ROGDI may interact with DISC1 which is involved in neuronal proliferation and migration and differentiation of cortical interneurons. All ROGDI mutations which include frameshift, nonsense, and splice site mutations cause premature mRNA degradation or protein structure alteration that results in the lack of function of the protein. Frameshift Mutations One family had a frameshift mutation called c.366dupA. This duplication that caused the frameshift resulted in a premature stop codon in the ROGDI gene after the 19th amino acid. Nonsense Mutation A mutation called c.507delC which is the deletion of a cytosine at position 507 resulted in a nonsense mutation. A nonsense mutation is a point mutation that results in a premature stop codon. Five affected families contained the nonsense mutation called c.268C>T where a thymine is in the place of a cytosine at position 268 on exon 5. Splice-Site Mutation There are three different splice-site mutations that have been identified in KTS patients. One is known as c.45+9_45+20del and prevents the recognition of the splice site at intron 1. This results in a frameshift in the gene causing a premature stop codon in exon 3. Another is known as c.531+5G>C. This mutation destroys the splice acceptor and donor sites resulting in an in-frame deletion. The protein resulting from this gene has a highly altered structure and is not functional. The last is known as c.532=2A>T and occurs in intron 7. This also destroys the splice donor and acceptor sites due to the inclusion of 83 extra nucleotides before exon 8 in the mRNA. This mutation causes non-sense mediated decay of the mRNA. Related Gene Mutations Due to the fact that not all 10 affected families were found to have a mutation in ROGDI, and the noted variability between affected individuals, it is possible this syndrome is a contiguous gene syndrome. A contiguous gene syndrome occurs when multiple genes are affected by an alteration in a short chromosomal region. Amelogenesis Imperfecta is known to be caused by other genetic mutations. Two examples are in chromosome 4 open reading frame 26 (C4orf26) and in the SLC24A4 which both segregate in an autosomal recessive manner.
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Imerslund–Gräsbeck syndrome
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Schöpf–Schulz–Passarge syndrome
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Melkersson–Rosenthal syndrome
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König's syndrome