Media coverage
(Zaobao Dec 2019)
Gitelman syndrome is a very rare medical condition in which the kidneys are unable to retain important salts (electrolytes) within the body, including potassium and magnesium. It is an autosomal recessive disorder, and most cases are linked to inactivating mutations of a gene known as SLC12A3 resulting in functional loss of the thiazide-sensitive sodium-chloride symporter.
This research work was started as a result of a patient - 29 years of age at that time, who first consulted the clinic for bleeding in the stools. She had been diagnosed with GItelman syndrome since the age of 9, and has to take hundreds of pills a day to replenish her electrolytes. Further investigations showed multiple polyps in her large intestines as well as synchronous cancers - which were successfully removed with surgery. What was highly unusual in this case was the occurence of multiple cancers in Gitelman syndrome, which had never been reported until now.
Using whole-exome sequencing, we confirmed germline compound heterozygous mutations of c.179C > T and c.1326C > G in SLC12A3, and in addition, identified a monoallelic (single copy) germline c.934-2A > G splice site mutation in MUTYH. MUTYH is a gene important for DNA damage repair - typically, two defective copies of the gene are required for an increased risk in cancer. In lymphoblastoid cell lines derived from the patient, we showed that magnesium deficiency potentiated oxidative DNA damage. Given these results, we postulate that monoallelic MUTYH mutations may manifest in the presence of cooperative non-genetic mechanisms, in this case possibly magnesium deficiency from Gitelman syndrome.
In other words, it is likely that chronic magnesium deficiency (due to Gitelman syndrome) PLUS a single defect in MUTYH may had increased the risk of early onset cancer development in this patient. This patient was advised to be strictly compliant to her magnesium supplements. She remains cancer free more than 5 years from surgery.
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