SLC1A4 — Spastic tetraplegia, thin corpus callosum, and progressive microcephaly syndrome

SLC1A4 encodes the ASCT1 neutral amino acid transporter essential for L-serine uptake into neurons. Biallelic pathogenic variants in SLC1A4 cause SPATCCM, a rare autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly, spastic tetraplegia, thin corpus callosum, and seizures.

Since the initial identification of a founder p.Glu256Lys allele in Ashkenazi Jewish families, at least eleven probands from over six unrelated families have been reported with biallelic SLC1A4 variants (PMID:25930971; PMID:26138499; PMID:26041762; PMID:27193218; PMID:31763347; PMID:37502193). Segregation analyses in six affected sibships confirm autosomal recessive inheritance (PMID:25930971; PMID:31763347; PMID:37502193).

The allelic spectrum includes recurrent missense p.Glu256Lys, nonsense and frameshift alleles such as c.573T>G (p.Tyr191Ter), c.944_945del (p.Leu315fs), c.971delA (p.Asn324ThrfsTer29), and the missense c.542C>T (p.Ser181Phe). The p.Glu256Lys founder allele has a carrier frequency of 0.7% in Ashkenazi individuals (PMID:26041762).

Functional assays demonstrate that p.Glu256Lys and p.Arg457Trp abolish or markedly reduce L-serine transport in heterologous systems (PMID:26041762). Cryo-EM structure and molecular dynamics simulations reveal that disease-associated mutations destabilize ASCT1 and impede substrate cycling (PMID:34630942).

A knock-in mouse model harboring p.Glu256Lys exhibits microcephaly, thin corpus callosum, and altered D-serine uptake, faithfully recapitulating human SPATCCM, while oral L-serine supplementation rescues brain serine levels and ameliorates microcephaly (PMID:37642681; PMID:38662784).

These data establish a loss-of-function mechanism underlying SPATCCM and support clinical sequencing of SLC1A4 in infants with unexplained microcephaly and spasticity. L-serine supplementation represents a rational therapeutic strategy.

References

• Clinical genetics | 2015 | A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly. PMID:25930971
• Clinical genetics | 2015 | SLC1A4 mutations cause a novel disorder of intellectual disability, progressive microcephaly, spasticity and thin corpus callosum. PMID:26138499
• Journal of medical genetics | 2015 | Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination. PMID:26041762
• Journal of human genetics | 2016 | Novel European SLC1A4 variant: infantile spasms and population ancestry analysis. PMID:27193218
• Child neurology open | 2019 | A Novel SLC1A4 Mutation (p.Y191) Causes Spastic Tetraplegia, Thin Corpus Callosum, and Progressive Microcephaly (SPATCCM) With Seizure Disorder.* PMID:31763347
• Frontiers in pediatrics | 2023 | Novel compound heterozygous variants (c.971delA/c.542C>T) in SLC1A4 causes spastic tetraplegia, thin corpus callosum, and progressive microcephaly: a case report and mutational analysis. PMID:37502193
• Computational and structural biotechnology journal | 2021 | A structural view onto disease-linked mutations in the human neutral amino acid exchanger ASCT1. PMID:34630942
• Mammalian genome : official journal of the International Mammalian Genome Society | 2023 | Generation and characterization of a knock-in mouse model for spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM). PMID:37642681
• Brain : a journal of neurology | 2024 | A new type of blood-brain barrier aminoacidopathy underlies metabolic microcephaly associated with SLC1A4 mutations. PMID:38662784

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