**5.** *TSC1* **and** *TSC2* **genes variation spectrum**

Table 3 and 4 summarized updates on the variation spectrum within *TSC1* and *TSC2* and review their characteristics. The information was accessed from the LOVD for Tuberous Sclerosis (http://chromium.liacs.nl/LOVD2/TSC/ home.php) on 3 April 2011 (Fokkema et al, 2005). There are 468 unique *TSC1* sequence variations and 1222 unique *TSC2* sequence variations reported. Tables 1 and 2 listed up all unique sequence variations of *TSC1* and *TSC2* respectively, along with their variation types and information of pathogenicity.


\*R/C = Reported/Concluded. "Reported Pathogenicity" refers to the pathogenicity as published by the authors in the original paper or as submitted to the LOVD-TSC database if the data has not been published. "Concluded Pathogenicity" refers to the pathogenicity that the curators of the database have assigned to the variant. (Personal Communication with the LOVD-TSC Database Curator; Dr. Rosemary Ekong). "-" = no known pathogenicity; "-?" = probably no pathogenicity; "+" = pathogenic; "+?" = probably pathogenic; "?" = unknown pathogenicity.

Table 3. *TSC1* sequence variations and their pathogenicity.

Table 3 and 4 summarized updates on the variation spectrum within *TSC1* and *TSC2* and review their characteristics. The information was accessed from the LOVD for Tuberous Sclerosis (http://chromium.liacs.nl/LOVD2/TSC/ home.php) on 3 April 2011 (Fokkema et al, 2005). There are 468 unique *TSC1* sequence variations and 1222 unique *TSC2* sequence variations reported. Tables 1 and 2 listed up all unique sequence variations of *TSC1* and

Substitution Insertion Deletion DuplicationInsertion /


\*R/C = Reported/Concluded. "Reported Pathogenicity" refers to the pathogenicity as published by the authors in the original paper or as submitted to the LOVD-TSC database if the data has not been published. "Concluded Pathogenicity" refers to the pathogenicity that the curators of the database have assigned to the variant. (Personal Communication with the LOVD-TSC Database Curator; Dr. Rosemary Ekong). "-" = no known pathogenicity; "-?" = probably no pathogenicity; "+" = pathogenic; "+?" =

probably pathogenic; "?" = unknown pathogenicity.

Table 3. *TSC1* sequence variations and their pathogenicity.

Deletion **Total** 

*TSC2* respectively, along with their variation types and information of pathogenicity.

**5.** *TSC1* **and** *TSC2* **genes variation spectrum** 

Types

Pathogenicity (R/C)\*


\*R/C = Reported/Concluded. "Reported Pathogenicity" refers to the pathogenicity as published by the authors in the original paper or as submitted to the LOVD-TSC database if the data has not been published. "Concluded Pathogenicity" refers to the pathogenicity that the curators of the database have assigned to the variant. (Personal Communication with the LOVD-TSC Database Curator; Dr. Rosemary Ekong). "-" = no known pathogenicity; "-?" = probably no pathogenicity; "+" = pathogenic; "+?" = probably pathogenic; "?" = unknown pathogenicity.

Table 4. *TSC2* sequence variations and their pathogenicity.

In *TSC1*, the most prevalent types of variations found are substitution (49.8%) followed by deletion (34.4%). Of 468 unique variations reported in *TSC1*, 73.5% (344) had their pathogenicity determined. In *TSC2*, the most prevalent types of variations found are also substitution (68.7%) followed by deletion (16.9%). Of 1222 unique variations reported in *TSC2*, only less than half (48%) had their pathogenicity determined. Different gene sizes of *TSC1* and *TSC2* may explain the fact that more variations occurred in *TSC2* than in *TSC1.*

Tuberous Sclerosis Complex 19

and two coiled-coil domains are necessary for its association with tuberin (van Slegtenhorst

Although *TSC1*- or *TSC2*-specific functions are possible, it seems that the predominant biochemical activity of these proteins is exerted by an equimolar complex, which regulates the state of GTP-loading of the rheb GTPase, and thereby regulates mTOR activation in the cell. As most hamartomas in TSC develop through a two-hit inactivation mechanisms (Knudson's hypothesis for tumor suppressor genes, including *TSC1* and *TSC2*), it appears likely that somatic mutations in *TSC1* are less common than those in *TSC2*, just as the rate of germline mutation in *TSC1* is much lower than that in *TSC2*. Thus, fewer and/or less severe

LOH is very common within TSC hamartomas, except for cardiac or brain. In both organs, study says that wildtype hamartin and tuberin are present. LOH is an event by which within the affected cells, the genomic DNA loss its heterozygosity, becoming homozygous for the mutation. In other cells (unaffected cells) the genomic DNA shows heterozygous for the mutation. To analyze the occurrence of LOH it is necessary to perform mutation analysis on the genomic DNA extracted from the affected cells as well as from the unaffected cells. After the discovery of *TSC1* and *TSC2* and their encoded proteins, several downstream protein cascades that might be affected by the pathogenesis of the disease, such as the

et al., 1997 and van Slegtenhorst et al., 1998).

clinical manifestations would be seen in *TSC1* patients.

Fig. 1. Hamartin and tuberin as tumor suppressor gene.

pathway of mTOR (mammalian target of rapamycin), were identified.

Perhaps because of more chances of the variations to occur along considerable length of intronic portions within *TSC2*, less pathogenicity variations can be conclusively determined. The tables showed that of 1690 *TSC1* and *TSC2* variations reported, only 27.7% (468) were found in *TSC1*. There are some explanations for the fact that up to date more *TSC2*  variations were found compared to *TSC1*:

