TP73 gene mutations indicate risk for ALS

An analysis of exome sequences in patients with ALS and healthy controls “strongly” indicated that variants in the TP73 gene are associated with risk for ALS, according to study results published in Neurology.

“While known gene variants are critical determinants of 68% of familial ALS cases, they only account for 17% of sporadic ALS, yet up to 61% of sporadic ALS is believed to be influenced by genetic factors,” Lynn B. Jorde, PhD, chair of the department of human genetics at the University of Utah, said in a press release. “Our study has identified a new genetic risk factor for sporadic ALS, rare mutations in the gene TP73. We also found that mutations of this gene have a damaging effect on protein function and that the protein created by this gene is necessary for nerve cell health.”

Jorde and colleagues sought to identify specific loci associated with ALS risk by performing whole exome sequencing on TP73 mutations through blood samples. The researchers first analyzed samples provided by 87 people with sporadic ALS. After finding five individuals with heterozygous rare, nonsynonymous TP73 mutations in this group, the researchers then evaluated a larger, independent group of 2,800 people with sporadic ALS. The analysis identified 19 additional individuals with “rare, deleterious” mutations in TP73. An analysis of a control group of 324 people without ALS yielded no mutations.

Following the blood analysis, Jorde and colleagues conducted C2C12 myoblast differentiation assays, characterization of myotube appearance and immunoprecipitation of p53-p73 complexes in vitro. They also used CRISPR/Cas9 targeting of zebrafish TP73 to assess motor neuron number and axon morphology in vivo.

The gene mutations produced abnormal differentiation and increased apoptosis in the myoblast differentiation assay, with abnormal myotube appearance, according to the researchers. Moreover, immunoprecipitation of mutant deltaN-p73 showed that mutations hindered deltaN-p73’s ability to bind p53. CRISPR targeting generated impaired motor neuron development and abnormal axonal morphology, suggestive of ALS pathology.

The findings indicate that TP73 is a novel ALS risk gene and that apoptosis in motor neurons “may play an important role in ALS pathology,” Jorde and colleagues wrote.

“Our research indicates that cell death linked to these mutations may be [a] factor in the development of ALS,” Jorde said in the press release. “This discovery provides a new target for researchers working to develop therapies to slow or even stop the progression of ALS.”

Reference:

American Academy of Neurology. Researchers identify new gene that may increase risk of ALS. Available at: https://www.aan.com/PressRoom/Home/PressRelease/4903. Accessed June 16, 2021.