RBM28 – ANE syndrome

RBM28 has been implicated in ANE syndrome, a complex disorder characterized by multiple endocrine deficiencies and additional systemic features. Patients typically exhibit signs of combined pituitary hormone deficiency, including growth hormone deficiency, hypogonadism, and adrenocorticotropic hormone deficiency. These clinical findings necessitate long‑term hormonal monitoring to manage the evolving endocrine dysfunction.

Genetic evidence strongly supports the association of RBM28 with ANE syndrome. In the initial study, five affected male siblings were found to harbor a homozygous loss‑of‑function mutation, providing compelling segregation evidence (PMID:20231366). A subsequent independent report identified a second family along with a pediatric case carrying biallelic splicing variants, further reinforcing the genetic etiology (PMID:33941690).

Molecular evaluation identified the recurrent coding change, c.1052T>C (p.Leu351Pro), as a key pathogenic variant. This variant, along with additional splicing mutations, has been observed across at least seven probands, underscoring the consistency of the genetic findings. The recurrence of the p.Leu351Pro alteration across unrelated cases provides additional merit to the gene‑disease association.

Functional studies provide complementary evidence to the genetic data. Yeast model analyses and protein folding assays demonstrated that RBM28 mutations lead to defective ribosomal RNA processing and impaired assembly of the nucleolar large ribosomal subunit (PMID:27077951). These disruptions in nucleolar function correlate well with the endocrine deficits observed in patients, offering a mechanistic explanation for the phenotype.

Integrating these genetic and functional datasets, the evidence indicates that RBM28 mutations underlie the pathogenesis of ANE syndrome. The convergence of segregation data, recurrent mutation findings, and consistent functional impairment establishes a robust framework for diagnostic decision‑making, facilitating both clinical and commercial applications.

Key Take‑home sentence: Genetic testing for RBM28 mutations is critical for diagnosing ANE syndrome and enabling appropriate endocrine management.

References

• European journal of endocrinology • 2010 • ANE syndrome caused by mutated RBM28 gene: a novel etiology of combined pituitary hormone deficiency PMID:20231366
• Proceedings of the National Academy of Sciences of the United States of America • 2021 • Biallelic splicing variants in the nucleolar 60S assembly factor RBM28 cause the ribosomopathy ANE syndrome PMID:33941690
• eLife • 2016 • The molecular basis for ANE syndrome revealed by the large ribosomal subunit processome interactome PMID:27077951

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