New Mutation in TSEN2 Gene Associated With aHUS, Study Finds

Vanda Pinto, PhD avatar

by Vanda Pinto, PhD |

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A newly identified mutation in the TSEN2 gene that causes craniofacial abnormalities, intellectual and developmental disabilities, as well as atypical hemolytic uremic syndrome (aHUS), was found in six children, a genetic study shows.

Based on these observations, scientists proposed naming the new syndrome “TRACK” which stands for TSEN2-related atypical hemolytic uremic syndrome, craniofacial malformations, kidney failure.

The study, “A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome,” was published in the journal Clinical Genetics.

In aHUS, when cells lining blood vessels become injured or activated — a phenomenon known as endothelial cell dysfunction — they lose their anti-blood clotting abilities, resulting in the formation of blood clots. Overactive complement, a part of the immune system, can also trigger endothelial cell dysfunction and increase the formation of blood clots. These blood clots ultimately cause organ damage, especially to the kidneys.

Genetic causes are associated with the majority of aHUS cases, and most of the disease-predisposing mutations are found in genes that regulate the activity of the complement cascade. However, in 30%–40% of people with aHUS, the underlying genetic cause is unknown.

Now, a team of researchers in Turkey, China, and the U.S. has described a new mutation in the TSEN2 gene that was identified in six children from four blood-related families.

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TSEN2 contains instructions for making one of the subunits of the transfer RNA (tRNA) splicing endonuclease, an enzyme that removes introns — regions in a gene that have no protein-coding information — from tRNA genes to generate functional tRNAs.

tRNAs are molecules involved in the production of new proteins that are responsible for assembling protein building blocks called amino acids.

Scientists first identified four children — a 5-year-old boy and three girls ages 2–10 — in a large group of patients with aHUS, who besides having kidney injury also had a small head circumference (microcephaly), several craniofacial malformations, along with intellectual and developmental delays.

Genetic screening showed that none of the children had mutations in the genes most commonly associated with aHUS, including CFH, CFI, CFB, C3, CD46 (MCP), CFHR1-5, DGKE, PLG, and THBD, or anti-complement factor H antibodies.

Only one genetic variant, called a c.914-5T>A, was discovered in an intronic region of the TSEN2 gene. This mutation was homozygous, meaning that it was found in both gene copies (one inherited from each parent).

Later, the authors identified two more children, boys ages 4 and 10, with similar features and symptoms who also carried the same mutation.

Further analysis revealed the variant resulted in the production of abnormal versions of TSEN2 messenger RNA (mRNA) — the molecule that is used as a template to make the TSEN2 protein. While some of TSEN2 mRNAs were normal, others skipped exon 10, a protein coding region, and others would contain instructions for two extra amino acids.

In genetically altered zebrafish with a similar type of mutation (skipped exon 10 in TSEN2), authors observed blood cells “pooling,” a small brain, kidney cysts, and swelling. Constriction of the common cardinal vein, an enlarged pericardium — the membrane that surrounds the heart — and increased branching of blood vessels were noted as other features caused by the mutation.

“We have identified a novel syndrome accompanied by aHUS suggesting the existence of a link between tRNA biology and vascular endothelium [healthy balance], which we propose to name with the acronym TRACK syndrome (TSEN2 Related Atypical hemolytic uremic syndrome, Craniofacial malformations, Kidney failure),” the authors wrote. “Further studies, possibly aimed to analyze neuron- and endothelium-specific mRNAs will be required to uncover uncharacterized functions of TSEN2 and the mechanisms that lead to [central nervous system] and vascular endothelial defects.”