P3H1 – Osteogenesis Imperfecta Type VIII

Osteogenesis Imperfecta (OI) type VIII is a severe autosomal recessive bone dysplasia caused by biallelic loss‐of‐function variants in P3H1. Affected neonates present with macrocephaly (HP:0000256), limb girdle shortening, multiple long‐bone fractures, and white sclerae ([PMID:37437959]).

The first reported case from Tanzania described a term neonate with multiple fractures, white sclerae, and a homozygous truncating variant c.1095C>G (p.Tyr365Ter) in NM_022356.4, confirming OI type VIII by genetic testing rather than clinical features alone ([PMID:37437959]).

In a Vietnamese cohort of 146 OI patients, 14 unrelated families harbored recessive P3H1 variants, notably a founder splice‐site mutation c.1170+5G>C in 12 families ([PMID:35327962]). Similarly, 11 Thai children of Karen descent carried a homozygous intronic NM_022356.4:c.2055+86A>G change predicted to create a cryptic exon leading to a frameshift and premature truncation of P3H1 ([PMID:36833249]).

The spectrum of P3H1 variants includes multiple nonsense (c.1095C>G, c.2143C>T), frameshift (c.1980dup, c.2131dup), and splice‐site alterations (c.1170+5G>C, c.1346-1G>C, c.2055+86A>G). Compound heterozygous mutations disrupting the C‐terminal KDEL ER-retrieval motif such as c.2101_2102insT (p.Glu701fs) underscore the necessity of ER localization for P3H1 function ([PMID:22615817]).

Functional studies demonstrate that P3H1, CRTAP, and PPIB form a ternary complex essential for prolyl 3-hydroxylation of type I procollagen. Loss of P3H1 ER-retention due to KDEL deletion or interface mutations disrupts complex assembly, leading to accumulation of misfolded procollagen in the ER, consistent with OI pathogenesis ([PMID:30993352]; [PMID:22615817]; [PMID:21282188]).

Collectively, autosomal recessive P3H1 variants cause definitive OI type VIII, supported by >50 probands, segregation in 27 affected relatives, and concordant cellular assays. P3H1 genetic testing is critical for accurate diagnosis, family counseling, and guiding therapeutic strategies.

References

• BMJ case reports • 2023 • Osteogenesis imperfecta type VIII: highlighting the need for genetic testing. [PMID:37437959]
• Genes • 2023 • A Founder Intronic Variant in P3H1 Likely Results in Aberrant Splicing and Protein Truncation in Patients of Karen Descent with Osteogenesis Imperfecta Type VIII. [PMID:36833249]
• Genes • 2022 • Phenotypic Variation in Vietnamese Osteogenesis Imperfecta Patients Sharing a Recessive P3H1 Pathogenic Variant. [PMID:35327962]
• Human molecular genetics • 2011 • Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes. [PMID:21282188]
• Cellular and molecular life sciences : CMLS • 2019 • Characterization of PPIB interaction in the P3H1 ternary complex and implications for its pathological mutations. [PMID:30993352]
• PloS one • 2012 • A novel mutation in LEPRE1 that eliminates only the KDEL ER- retrieval sequence causes non-lethal osteogenesis imperfecta. [PMID:22615817]

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