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Orphan Gene Linked to Neurodevelopmental Disorder Characterized by Hearing Loss

NEW YORK — Biallelic variants affecting the orphan gene SPATA5L1 lead to a neurodevelopmental disorder that comes with hearing loss, according to a new study that also hints at a role for the gene in cell surface adhesion, DNA replication, and mitosis. 

Previously, homozygous or compound heterozygous variants affecting a gene called SPATA5 had been linked to a neurodevelopmental disorder characterized by microcephaly, intellectual disability, and hearing loss, among other clinical features. A new sequencing screen of other individuals with sensorineural hearing loss and cerebral palsy has now identified biallelic, likely pathogenic variants in a paralog of SPATA5, dubbed SPATA5L1, that contribute to their neurodevelopmental disorder. 

An international team of researchers led by the University of Arizona's Michael Kruer described the SPATA5L1-associated condition in the American Journal of Human Genetics and examined how these variants destabilized the protein encoded by the gene. Additionally, transcriptomic analysis indicated a role for SPATA5L1 in cell surface adhesion receptor function as well as in DNA replication. 

"Collectively, our results indicate that biallelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype," Kruer and his colleagues wrote in their paper. 

Through their sequencing screen of individuals with sensorineural hearing loss and cerebral palsy, the researchers identified biallelic, predicted deleterious variants in SPATA5L1 associated with the condition. Using the GeneMatcher service, they connected with other researchers around the world interested in the same gene. Overall, they uncovered 28 unique SPATA5L1 variants among 47 individuals from 26 unrelated families. Of these variants, 25 were present as compound heterozygous and three as homozygous variants.

All the affected individuals with biallelic variants presented with some hearing loss, ranging from mild to severe, and about half also had neurological features such as developmental delay or intellectual disability and seizures. At the same time, most affected individuals also had a movement disorder — commonly spasticity or dystonia — and about half had microcephaly. 

Through neuroimaging studies, the researchers noted that some affected individuals had decreased cerebral volume, a thin corpus callosum, and decreased white matter volume. 

SPATA5L1 belongs to the AAA+ ATPases protein superfamily, a diverse group of ATPases, and of the 13 variants the researchers analyzed, 11 were predicted to have a deleterious effect on protein structure. They found that, typically, the SPATA5L1 protein localizes to neurons and glial cells in the brain during embryogenesis and adult development. An analysis in rats additionally found that the protein localized to inner and outer hair cells within the ear, indicating that the protein-disrupting variants could affect the typical protein function there to lead to hearing loss. 

A transcriptomic analysis of fibroblasts from affected and unaffected individuals further found that they could be distinguished based on their set of differentially expressed genes. Affected individuals had a number of significantly downregulated genes.

This set of downregulated genes converged on certain networks, the researchers noted, including pathways involved in mitosis and DNA replication, as well as those affecting adhesion receptors. This, the researchers noted, suggests SPATA5L1 has a role in mitosis and DNA replication, adding that other members of the same ATPase protein family also have roles in mitosis, DNA replication, metabolism, and repair processes. 

"Although SPATA5L1 is an orphan gene, our transcriptomic studies provide some clues as to its function," they wrote in their paper, later adding that although their "studies support a role for SPATA5L1 in DNA replication, further experimental studies will be required to support or refute this hypothesis." 

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