POP1 – anauxetic dysplasia

POP1 encodes a core component of the RNase MRP complex and biallelic loss-of-function or missense variants have been implicated in anauxetic dysplasia (AAD; MONDO:0011773), a rare autosomal recessive skeletal dysplasia allelic to cartilage-hair hypoplasia (MONDO:0009595). Affected individuals present with severe short stature, metaphyseal and epiphyseal dysplasia, and brachydactyly, with occasional multisystem involvement in expanded phenotypes.

Genetic Evidence

AAD due to POP1 mutations follows an autosomal recessive inheritance pattern with at least 8 probands across 4 unrelated families demonstrating biallelic POP1 variants (2 siblings in a quartet family [PMID:21455487], 1 consanguineous case [PMID:27380734], 2 individuals in a phenotypic spectrum study [PMID:28067412], and 3 cases in a developmental‐delay cohort [PMID:38351533]). Segregation of compound heterozygous alleles was observed in two affected sisters in the quartet family ([PMID:21455487]).

Variant Spectrum

Reported variants include missense (e.g., c.1744C>T (p.Pro582Ser) ([PMID:27380734]), c.449G>T (p.Arg150Leu) ([PMID:38351533]), c.1531G>T (p.Asp511Tyr) ([PMID:28067412])), loss-of-function (e.g., c.1537C>T (p.Arg513Ter) ([PMID:21455487])), frameshift and splice-site changes. The recurrent p.Pro582Ser allele has been identified in independent pedigrees ([PMID:28067412]).

Phenotypic Spectrum

Classic AAD manifests as extreme short stature with rhizomelic limb shortening, generalized joint hypermobility, metaphyseal dysplasia of long bones, vertebral body modifications, and severe brachydactyly ([PMID:21455487]). Neurodevelopmental involvement is variable: three siblings with global developmental delay, microcephaly and autism expanded the phenotype ([PMID:38351533]).

Functional / Experimental Evidence

POP1 mutations disrupt RNase MRP complex integrity and ribonucleoprotein activity, leading to reduced RMRP RNA abundance, accumulation of pre-5.8S rRNA, and impaired cellular proliferation ([PMID:21455487], [PMID:28067412]). These findings support a loss-of-function mechanism.

Integration & Clinical Utility

The combination of multiple unrelated probands with biallelic POP1 variants, consistent autosomal recessive segregation, diverse variant classes, and concordant functional data establishes a strong gene–disease relationship. POP1 sequencing should be included in diagnostic panels for severe skeletal dysplasia and related neurodevelopmental presentations.

Key take-home: Biallelic POP1 variants cause anauxetic dysplasia via a loss-of-function mechanism, supporting their inclusion in genetic testing for severe skeletal dysplasias.

References

• American journal of medical genetics. Part A • 2016 • Further evidence of POP1 mutations as the cause of anauxetic dysplasia. PMID:27380734
• PLoS genetics • 2011 • Whole-exome re-sequencing in a family quartet identifies POP1 mutations as the cause of a novel skeletal dysplasia. PMID:21455487
• Clinical genetics • 2017 • Broadening the phenotypic spectrum of POP1-skeletal dysplasias: identification of POP1 mutations in a mild and severe skeletal dysplasia. PMID:28067412
• Clinical genetics • 2024 • Novel phenotype associated with homozygous likely pathogenic variant in the POP1 gene. PMID:38351533

Evidence Based Scoring (AI generated)