Computational and mitochondrial functional studies of novel compound heterozygous variants in SPATA5 gene support a causal link with epileptogenic encephalopathy

Abstract

The SPATA5 gene encodes a 892 amino-acids long protein that has a putative mitochondrial targeting sequence and has been proposed to function in maintenance of mitochondrial function and integrity during mouse spermatogenesis. Several studies have associated homozygous or compound heterozygous mutations in SPATA5 gene to microcephaly, intellectual disability, seizures and hearing loss. This suggests a role of the SPATA5 gene also in neuronal development. Recently, our group presented results validating the use of blood cells for the assessment of mitochondrial function for diagnosis and follow-up of mitochondrial disease, minimizing the need for invasive procedures such as muscle biopsy. In this study, we were able to diagnose a patient with epileptogenic encephalopathy using next generation sequencing. We found two novel compound heterozygous variants in SPATA5 that are most likely causative. To analyze the impact of SPATA5 mutations on mitochondrial functional studies directly on the patients' mononuclear cells and platelets were undertaken. Oxygen consumption rates in platelets and PBMCs were impaired in the patient when compared to a healthy control. Also, a decrease in mitochondrial mass was observed in the patient monocytes with respect to the control. This suggests a true pathogenic effect of the mutations in mitochondrial function, especially in energy production and possibly biogenesis, leading to the observed phenotype.

An inappropriate decline in ribosome levels drives a diverse set of neurodevelopmental disorders

“…These phenotypes are strikingly similar those associated with alleles in other components of the AIRIM complex, including AFG2A, AFG2B, and CINP [19][20][21][22]24,25,31 and are predominantly associated with global developmental delay, intellectual disability, muscular hypotonia, limb spasticity, dystonia, microcephaly, infantile seizures, as well as hearing and vision impairment (see Figure S1E for comparative summary). Importantly, patients that carry AFG2A and AFG2B allelic variants commonly exhibit similar neuroimaging features [21][22][23][24] .…”

“…Additional studies have further implicated human AFG2A and AFG2B in ribosome production 17,18 . Strikingly, human genetic studies have identified a growing number of allelic variants in AFG2A, AFG2B, and CINP that are specifically associated with a range of NDDs, including intellectual disabilities, seizures, hearing loss, and microcephaly [19][20][21][22][23][24][25] . Here, we identify new variants in AIRIM associated with a similar range of neurological phenotypes.…”

Electroacoustic Hearing Correction in the Syndrome of Epilepsy, Hearing Loss and Mental Retardation Associated with Mutations in the SPATA5 Gene: A Case Report

“…Мутации в гене SPATA5 связаны с микроцефалией, умственной отсталостью, судорогами и тугоухостью, что заставляет выдвинуть предположение о роли гена SPATA5 не только в сперматогенезе, но и в развитии нейронов и росте аксонов, и имеют аутосомно-рецессивный тип наследования [16]. Дефицит SPATA5 приводит к уменьшению количества митохондрий, в связи с чем уменьшается продукция АТФ на окончаниях аксонов и нарушается аксоногенез [14,15].…”