LAS1L – Distal Spinal Muscular Atrophy

LAS1L has emerged as a critical gene in the context of autosomal recessive distal spinal muscular atrophy 1. Multiple independent studies have reported patients presenting with severe neuromuscular phenotypes, including spinal muscular atrophy with respiratory distress (SMARD) and congenital lethal motor neuron disease (PMID:35627110, PMID:24647030).

In the reported cases, genetic analysis identified two different variants in LAS1L. One study described an eighteen‑month‑old boy with a SMARD phenotype harboring a hemizygous synonymous variant, c.846G>C (p.Thr282=), which was inherited from an unaffected mother and proposed to disrupt RNA splicing (PMID:35627110). A separate report identified a de novo variant, c.1613G>A (p.Ser538Asn), in a patient with congenital lethal motor neuron disease (PMID:24647030).

The genetic evidence supports an autosomal recessive inheritance pattern for distal spinal muscular atrophy 1. Although the c.846G>C (p.Thr282=) variant is synonymous at face value, functional assays including qPCR, deep sequencing, and splicing analysis have demonstrated its deleterious impact on RNA processing. This variant, along with the reported c.1613G>A (p.Ser538Asn), expands the spectrum of LAS1L alterations that can disrupt its critical role in ribosome biogenesis (PMID:35627110, PMID:24647030).

Functional studies have reinforced the pathogenicity of LAS1L mutations. Experiments in zebrafish using morpholino-mediated knockdown and reconstitution assays have shown that reduced LAS1L activity leads to impaired pre-rRNA processing and neuromuscular defects. Additionally, in vitro assays published in The Journal of Biological Chemistry detail how dual HEPN nuclease motifs of LAS1L are essential for RNA cleavage, emphasizing the gene’s role in maintaining ribosomal integrity (PMID:32220933).

Some conflicting aspects have emerged regarding the mode of inheritance, with one report describing a de novo mutation and labeling LAS1L as X‑linked. However, the disease context provided—autosomal recessive distal spinal muscular atrophy 1—and the aggregation of data from multiple independent studies support a strong overall association between LAS1L mutations and the neuromuscular phenotype.

Collectively, the integration of genetic and functional evidence provides compelling support for the involvement of LAS1L in distal spinal muscular atrophy 1. The convergence of case reports, segregation data, and experimental validation underscores the clinical utility of assessing LAS1L variants in patients with SMARD‑like symptoms. Key take‑home: precise molecular diagnosis of LAS1L splicing defects can substantially inform diagnostic decision‑making and potentially guide targeted therapeutic strategies.

References

• Genes • 2022 • Severe Infantile Axonal Neuropathy with Respiratory Failure Caused by Novel Mutation in X‑Linked LAS1L Gene PMID:35627110
• Neurology • 2014 • Congenital Lethal Motor Neuron Disease with a Novel Defect in Ribosome Biogenesis PMID:24647030
• The Journal of Biological Chemistry • 2020 • It takes two (Las1 HEPN endoribonuclease domains) to cut RNA correctly PMID:32220933

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