PYCR1 – Autosomal Recessive Cutis Laxa Type 2B

PYCR1 encodes pyrroline-5-carboxylate reductase 1 (P5CR1), a mitochondrial enzyme catalyzing the final step of proline biosynthesis. Biallelic variants in PYCR1 cause Autosomal recessive cutis laxa type 2B, a segmental progeroid disorder with loose skin, triangular facial gestalt, hypotonia, and growth retardation. The inheritance is autosomal recessive, and onset is typically in utero or early infancy. This gene–disease link is defined by multiple independent families with consistent phenotypes and laboratory confirmation of disrupted proline metabolism. Comprehensive evaluation of genetic and functional data supports a strong gene–disease relationship.

A seminal multi-patient study described 33 individuals from 27 unrelated families harboring PYCR1 variants with initial diagnoses including wrinkly skin syndrome, geroderma osteodysplasticum, or progeroid syndromes (PMID:24035636). Distinctive hallmarks were intrauterine growth retardation and hypotonia, along with a triangular facial gestalt and psychomotor delay. A 2011 case report of four affected siblings with a homozygous PYCR1 mutation noted phenotypic overlap with geroderma osteodysplasticum and suggested reclassification from ARCL2B to geroderma osteodysplasticum (PMID:21204221). Nevertheless, the systematic comparison across larger cohorts reaffirmed ARCL2B as a discrete PYCR1-related entity.

Genetic evidence encompasses 20 distinct PYCR1 variants identified in ARCL2B patients, including missense substitutions, canonical splice-site mutations, and a single nonsense allele, with clusters in exons 4–6 (PMID:24035636). Homozygous or compound heterozygous genotypes segregated with disease, often in consanguineous families. Recurrent founder alleles were not apparent, and carrier frequency remains low in population databases. The variant spectrum reaches the ClinGen genetic scoring cap, reflecting robust diagnostic yield.

Segregation analysis across the 27 families demonstrated co-segregation of damaging PYCR1 alleles with ARCL2B in multiple siblings, consistent with autosomal recessive inheritance. Although specific counts of affected relatives beyond probands were seldom detailed, all reported families exhibited complete penetrance among homozygotes. No heterozygous carriers displayed overt features, supporting a loss-of-function mechanism.

Functional assays corroborate pathogenicity: the p.Arg119Gly mutant (c.355C>G) shows markedly reduced enzymatic activity and thermal stability in vitro (PMID:28194412), while in silico and molecular dynamics analyses of p.Gly206Trp predict disrupted cofactor binding and increased rigidity at the catalytic site (PMID:27677826). Together, these data support a loss-of-function mechanism via protein destabilization and impaired proline synthesis.

In summary, the convergence of extensive multi-family genotyping, co-segregation of recessive alleles, and concordant biochemical impairment establishes a Strong clinical validity for the PYCR1–ARCL2B association. Functional evidence is Moderate, reflecting robust in vitro and computational studies. PYCR1 genetic testing yields high diagnostic utility in infants with cutis laxa and growth delay, enabling accurate prognosis and genetic counseling.

References

• American Journal of Medical Genetics Part A • 2011 • The phenotype caused by PYCR1 mutations corresponds to geroderma osteodysplasticum rather than autosomal recessive cutis laxa type 2 PMID:21204221
• Journal Unknown • Year Unknown • Autosomal recessive cutis laxa type 2B: clinical and molecular insights from 33 patients PMID:24035636
• BioMed Research International • 2017 • Effect of R119G Mutation on Human P5CR1 Dynamic Property and Enzymatic Activity PMID:28194412
• Journal of Biomolecular Structure & Dynamics • 2017 • In silico screening, molecular docking, and molecular dynamics studies of SNP-derived human P5CR mutants PMID:27677826

Evidence Based Scoring (AI generated)