GNPAT – Rhizomelic Chondrodysplasia Punctata Type 2

The GNPAT gene encodes dihydroxyacetonephosphate acyltransferase and is implicated in Rhizomelic chondrodysplasia punctata type 2, an autosomal recessive peroxisomal disorder characterized by short stature, severe intellectual disability, and epiphyseal stippling.

Autosomal recessive inheritance has been established through multiple consanguineous and non-consanguineous pedigrees, with 1 proband ([PMID:9843043]), 12 probands ([PMID:11237722]), and 6 additional probands ([PMID:21990100]), for a total of 19 probands demonstrating biallelic GNPAT variants.

Genetic analyses reveal a spectrum of nine distinct mutations in 12 unrelated patients, comprising 2 missense, 2 small deletions, 1 insertion, and 4 splice‐site alterations ([PMID:11237722]). A representative pathogenic allele is c.631C>T (p.Arg211Cys) ([PMID:11237722]).

Functional assays show residual DHAP-AT activity of 1.6% in patient fibroblasts ([PMID:9843043]), and transcript/protein studies of GNPAT variants confirm loss‐of‐function with residual enzyme function correlating with milder phenotypes ([PMID:21990100]).

Biallelic loss‐of‐function in GNPAT disrupts peroxisomal plasmalogen biosynthesis, leading to the characteristic skeletal dysplasia and neurodevelopmental impairment. No studies have refuted this association.

Children presenting with deficient growth, developmental delay, and epiphyseal stippling should be screened for peroxisomal plasmalogen deficiency, as identifying GNPAT variants has direct diagnostic and management implications. Key Take-home: GNPAT mutations cause RCDP type 2 via autosomal recessive loss‐of‐function, with well‐characterized biochemical and genetic hallmarks supporting clinical testing.

References

• American journal of medical genetics • 1998 • Developmental delay and growth failure caused by a peroxisomal disorder, dihydroxyacetonephosphate acyltransferase (DHAP-AT) deficiency. PMID:9843043
• Biochemical and biophysical research communications • 2001 • Etherphospholipid biosynthesis and dihydroxyactetone-phosphate acyltransferase: resolution of the genomic organization of the human gnpat gene and its use in the identification of novel mutations. PMID:11237722
• Human mutation • 2012 • Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3. PMID:21990100

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