SLC1A4 mutations cause a novel disorder of intellectual disability, progressive microcephaly, spasticity and thin corpus callosum

Abstract

Two unrelated patients, presenting with significant global developmental delay, severe progressive microcephaly, seizures, spasticity and thin corpus callosum (CC) underwent trio whole-exome sequencing. No candidate variant was found in any known genes related to the phenotype. However, crossing the data of the patients illustrated that they both manifested pathogenic variants in the SLC1A4 gene which codes the ASCT1 transporter of serine and other neutral amino acids. The Ashkenazi patient is homozygous for a deleterious missense c.766G>A, p.(E256K) mutation whereas the Ashkenazi-Iraqi patient is compound heterozygous for this mutation and a nonsense c.945delTT, p.(Leu315Hisfs*42) mutation. Structural prediction demonstrates truncation of significant portion of the protein by the nonsense mutation and speculates functional disruption by the missense mutation. Both mutations are extremely rare in general population databases, however, the missense mutation was found in heterozygous mode in 1:100 Jewish Ashkenazi controls suggesting a higher carrier rate among Ashkenazi Jews. We conclude that SLC1A4 is the disease causing gene of a novel neurologic disorder manifesting with significant intellectual disability, severe postnatal microcephaly, spasticity and thin CC. The role of SLC1A4 in the serine transport from astrocytes to neurons suggests a possible pathomechanism for this disease and implies a potential therapeutic approach.

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

“…It is expressed in astrocytes and neurons and represents the main uptake of L-Ser in neurons (Kanai et al, 2013). Missense mutations in the gene lead to neurological disorders with intellectual disability (Heimer et al, 2015) likely due to the alterations in the serine transport.…”

Serine biosynthesis and transport defects

“…Serine transport defect resulting from deficiency of the ASCT1, the main transporter for serine in the central nervous system, has been recently described in children with neurological manifestations that overlap with those observed in serine biosynthesis defects (Table 1) [4,3,5].…”

“…Common brain abnormalities in neuroimaging include thin corpus callosum, hypomyelination, and brain atrophy. Less frequent manifestations include irritability, hyperactivity, sleep disorder, stereotypies, and strabismus [4,3,5].…”

“…All previously reported children with serine transport defect were diagnosed through whole exome sequencing which identified biallelic mutations in the SLC1A4 gene encoding the ASCT1. Missense mutations and a frameshift deletion have been described in the SLC1A4 gene in the reported children with serine transport defect [4,3,5]. Homozygous p.E256K mutations have been identified in affected Ashkenazi Jewish children.…”

“…Mature neurons are unable to biosynthesize serine, and are thus dependent on serine uptake. Defects in serine transport have been recently described to result in phenotypes that overlap with serine biosynthesis defects [3][4][5]. In this review article, we discuss serine biosynthesis and its utilization, function, and neuronal transport.…”