Compound heterozygous SPATA5 variants in four families and functional studies of SPATA5 deficiency

Abstract

Variants in the SPATA5 gene were recently described in a cohort of patients with global developmental delay, sensorineural hearing loss, seizures, cortical visual impairment and microcephaly. SPATA5 protein localizes predominantly in the mitochondria and is proposed to be involved in mitochondrial function and brain developmental processes. However no functional studies have been performed. This study describes five patients with psychomotor developmental delay, microcephaly, epilepsy and hearing impairment, who were thought clinically to have a mitochondrial disease with subsequent whole-exome sequencing analysis detecting compound heterozygous variants in the SPATA5 gene. A summary of clinical data of all the SPATA5 patients reported in the literature confirms the characteristic phenotype. To assess SPATA5’s role in mitochondrial dynamics, functional studies were performed on rat cortical neurons. SPATA5-deficient neurons had a significant imbalance in the mitochondrial fusion-fission rate, impaired energy production and short axons. In conclusion, SPATA5 protein has an important role in mitochondrial dynamics and axonal growth. Biallelic variants in the SPATA5 gene can affect mitochondria in cortical neurons and should be considered in patients with a neurodegenerative disorder and/or with clinical presentation resembling a mitochondrial disorder.

PTBP2-dependent alternative splicing regulates protein transport and mitochondria morphology in post-meiotic germ cells.

“…SPATA5 was originally described as a spermatogenesis-associated factor with two-conserved ATPase modules and a mitochondria localization signal (Liu et al, 2000). In neurons, SPATA5 had a critical role in mitochondrial morphology, with Spata5 deficiency resulting in decreased mitochondrial fusion (Puusepp et al, 2018). Collectively, our observations indicate that PTBP2dependent AS regulation has an important role in maintaining proper mitochondrial dynamics in post-meiotic spermatids.…”

Effectiveness of whole exome sequencing in unsolved patients with a clinical suspicion of a mitochondrial disorder in Estonia

“…It results in an AR syndrome with severe global developmental delay, severe speech impairment, hearing loss, abnormal EEG, and microcephaly (OMIM 616577 ). Puusepp et al [ 28 ] 7 6 NDUFB11 (NM_019056.6) Hemizygous variant: c.328C > T, p.(Pro110Ser) Likely pathogenic variant: Absent in population databases (moderate evidence); Align GVGD, SIFT, MutationTaster predicts a deleterious effect, conserved region (supporting evidence); Decreased RCC I enzyme activity in our patient, located in the NADH domain (moderate evidence); de novo (strong evidence). Encodes a component of the RCC I.…”

4q27 deletion and 7q36.1 microduplication in a patient with multiple malformations and hearing loss: a case report

“…But the following studies of SPATA5 have suggested a role of the SPATA5 gene not only in neuronal development but also in spermatogenesis. It was dominantly cytosolic in cortical neurons [33][34][35][36]. The SPATA5 deficiency affects mitochondrial morphology and inhibits mitochondrial dynamics, delays neuronal development, and is also associated with decreased cellular ATP [36].…”

“…It was dominantly cytosolic in cortical neurons [33][34][35][36]. The SPATA5 deficiency affects mitochondrial morphology and inhibits mitochondrial dynamics, delays neuronal development, and is also associated with decreased cellular ATP [36]. All the patients with SPATA5 variants reported in the literature so far have presented with developmental delay starting in early infancy, 77% presented sensorineural hearing loss, 73% suffered from gastrointestinal problems such as GERD and feeding problem, and 67% was revealed with abnormal brain MRI including hypoplasia of corpus callosum [36].…”