Current genetic tests have difficulty locating the mutation in roughly 20% of individuals diagnosed with the disease. So far, it has been mapped to two genetic loci, "TSC1" and "TSC2". "TSC1" encodes for the protein hamartin, is located on chromosome 9 q34, and was discovered in 1997. "TSC2" encodes for the protein tuberin, is located on chromosome 16 p13.3, and was discovered in 1993. "TSC2" is contiguous with "PKD1", the gene involved in one form of polycystic kidney disease (PKD). Gross deletions affecting both genes may account for the 2% of individuals with TSC who also develop polycystic kidney disease in childhood. "TSC2" has been associated with a more severe form of TSC. However, the difference is subtle and cannot be used to identify the mutation clinically. Estimates of the proportion of TSC caused by "TSC2" range from 55% to 90%. "TSC1" and "TSC2" are both tumor suppressor genes that function according to Knudson's "two hit" hypothesis. That is, a second random mutation must occur before a tumor can develop. This explains why, despite its high penetrance, TSC has wide expressivity. Hamartin and tuberin function as a complex which is involved in the control of cell growth and cell division. The complex appears to interact with RHEB GTPase, thus sequestering it from activating mTOR signalling, part of the growth factor (insulin) signalling pathway. Thus, mutations at the "TSC1" and "TSC2" loci result in a loss of control of cell growth and cell division, and therefore a predisposition to forming tumors. TSC affects tissues from different germ layers. Cutaneous and visceral lesions may occur, including angiofibroma, cardiac rhabdomyomas, and renal angiomyolipomas. The central nervous system lesions seen in this disorder include hamartomas of the cortex, hamartomas of the ventricular walls, and subependymal giant cell tumors, which typically develop in the vicinity of the foramina of Monro. Molecular genetic studies have defined at least two loci for TSC. In "TSC1", the abnormality is localized on chromosome 9q34, but the nature of the gene protein, called hamartin, remains unclear.