Germline SAMD9L truncation variants trigger global translational repression.

Area of Science:

• Genetics
• Immunology
• Molecular Biology

Background:

• The sterile alpha motif domain-containing protein 9-like (SAMD9L) acts as an interferon-induced tumor suppressor.
• SAMD9L is linked to myeloid malignancies and immune deficiencies.
• Its precise role in multisystem disorders remained unclear.

Observation:

• A heterozygous de novo frameshift variant in SAMD9L was identified in an infant with B cell aplasia, autoinflammatory features, and fatal rhinovirus infection.
• Autopsy revealed absent B cells and loss of specific neuronal cell types (Langerhans and Purkinje cells).
• The variant caused a truncated SAMD9L protein with interferon treatment.

Findings:

• The truncated SAMD9L protein demonstrated a gain-of-function, inhibiting global protein synthesis by blocking translational elongation.
• A mutational scan revealed that specific stop-gain variants in SAMD9L also induce translational arrest.
• These translational suppressive variants did not affect mRNA transcription, suggesting lineage-specific sensitivities.

Implications:

• Interferon-triggered SAMD9L gain-of-function variants globally suppress protein translation.
• This mechanism underlies the complex phenotypes observed in patients with SAMD9L-related disorders.
• Understanding this pathway may inform therapeutic strategies for immune deficiencies and malignancies.