New CTSD Gene Variant Not Linked to Rare CLN10 Batten in Case

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by Forest Ray PhD |

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A new mutation found in the CTSD gene does not associate with the rare CLN10 form of Batten disease, despite occurring in a girl in China with CLN10-like symptoms, according to the results of a recent case report.

Nonetheless, the discovery of this new mutation “has significance” and will add to the database of knowledge about the inherited neurological condition, the researchers said.

The report, “The c.863A>G (p.Glu288Gly) variant of the CTSD gene is not associated with CLN10 disease,” was published in the journal Molecular Genomics & Genomic Medicine.

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Batten disease describes a group of 14 disorders also known as neuronal ceroid lipofuscinoses or NCLs. All involve an inability to properly break down a molecule called lipofuscin, which leads to progressive nerve damage. Brain cells are particularly sensitive to the toxic effects of accumulated lipofuscin, leading to symptoms such as seizures and progressive cognitive and motor difficulties.

Mutations in the CTSD gene underlie CLN10. This gene encodes the instructions for making the Cathepsin D (CatD) protein, which is highly active in the brain, where it helps to digest and recycle abnormal proteins.

Now, doctors at the Children’s Hospital of Chongqing Medical University, in China, evaluated a 15-year-old girl showing developmental delays and mental retardation. She showed signs of dementia, did not speak, walked slowly, exhibited poor reactions, and had a “severely reduced IQ.”

She had been determined to have no speaking ability at age 3 and suffered from frequent generalized convulsions before age 7.

Her medical team examined her brain for abnormalities using magnetic resonance imagining (MRI) and discovered signs of demyelination — the loss of an insulating protein called myelin around neurons, or nerve cells — despite her brain having a normal shape and size.

Because this finding suggested no underlying cause of the girl’s condition, the physicians continued to search for a genetic explanation. They performed a clinical exome sequencing test, which scans only the protein-coding parts of DNA for possible disease-causing mutations.

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Congenital Batten Disease (CLN10 Disease)

This analysis revealed six suspicious gene variants, including one in CTSD (c.863A>G). The medical team focused on this gene, due to its role in CLN10 and the similarities between that disorder and the girl’s symptoms.

To explore the effects of the girl’s CTSD mutation, the physicians copied that sequence in cells and studied how it affected the messenger RNA (mRNA) and protein levels of CatD, as compared with cells bearing the unaffected, or wild-type gene.

The two CTSD variants, however, resulted in no noticeable differences. Neither mRNA nor protein levels differed between cells with one or the other variant. Additionally, the location of CatD in both sets of cells, as well as its maturation and enzyme activity remained effectively the same in the context of either variant.

“It may be that other undiscovered mutations of other genes caused the patient to develop NCL-like symptoms,” the researchers suggested.

Although the results of this analysis did not lead to a diagnosis, the finding does contribute to the broader base of knowledge concerning CLN10 mutations, the team said.

“In conclusion,” the investigators wrote, “a benign missense variant in the CTSD gene was identified in a patient with generalized brain development disorder. The confirmation of this site has significance for the expansion of the NCL mutation database.”