RPL21 – Hypotrichosis Simplex

Ribosomal protein L21 is a component of the 60S ribosomal subunit required for protein synthesis. RPL21 (HGNC:10313) has been implicated in autosomal dominant nonsyndromic Hypotrichosis Simplex (MONDO:0018914), characterized by gradual scalp hair thinning without shaft abnormalities. Hypotrichosis simplex presents with progressive hair loss beginning in early childhood and leads to diffuse scalp sparseness. The disorder is genetically heterogeneous with multiple causative loci identified, and recent evidence establishes RPL21 as a novel disease gene in this spectrum.

Clinical validity per ClinGen criteria is classified as Moderate based on identification of the same pathogenic variant in three unrelated affected individuals, complete cosegregation in a multigenerational pedigree, and replication in an independent family (PMID:21412954). No conflicting or refuting reports have been described. The absence of functional characterization currently precludes a Strong rating, and additional experimental data would strengthen mechanistic insight.

In a Chinese family with autosomal dominant hypotrichosis simplex, exome sequencing of an index case identified a heterozygous NM_000982.4:c.95G>A (p.Arg32Gln) variant in RPL21 (PMID:21412954). The c.95G>A allele was absent from 200 ethnically matched controls, dbSNP, the YH database, and 1000 Genomes pilot data. Pedigree analysis demonstrated complete variant cosegregation with disease across all affected members and absence in unaffected relatives. These observations provide robust genetic support for the variant’s pathogenicity.

Further evidence came from detection of the identical c.95G>A (p.Arg32Gln) variant in two additional unrelated Chinese patients with hypotrichosis simplex (PMID:21412954). Replication in an independent pedigree excludes a private founder effect. No other coding or splice-site RPL21 variants have been reported in this disorder, suggesting a narrow mutational spectrum and potential mutational hotspot at this residue. Phenotypic presentation was consistent across carriers, with early-onset progressive diffuse hair thinning.

To date, no functional studies have assessed the impact of p.Arg32Gln on ribosomal assembly, translational fidelity, or hair follicle biology. The mechanism of pathogenicity remains speculative, with possible haploinsufficiency or dominant-negative effects impairing protein synthesis in follicular keratinocytes. Cellular or animal models and rescue experiments are lacking. Such data would be valuable to confirm the mechanistic basis and explore therapeutic strategies. Functional evidence is therefore considered Limited.

In summary, heterozygous RPL21 c.95G>A (p.Arg32Gln) demonstrates autosomal dominant inheritance, complete cosegregation, absence in controls, and replication across two families, fulfilling key genetic criteria for a Moderate ClinGen association. The lack of experimental functional validation limits mechanistic understanding and precludes a higher classification at this time. Integration of genetic data with the consistent clinical phenotype supports inclusion of RPL21 in diagnostic gene panels for nonsyndromic hypotrichosis simplex. Key take-home: Heterozygous c.95G>A (p.Arg32Gln) in RPL21 is a clinically actionable driver of autosomal dominant hypotrichosis simplex, enabling precise molecular diagnosis.

References

• Human Mutation | 2011 | Mutation in ribosomal protein L21 underlies hereditary hypotrichosis simplex. PMID:21412954

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