PTDSS1 – Lenz-Majewski hyperostotic dwarfism

Lenz-Majewski hyperostotic dwarfism (LMHD) is an ultra-rare autosomal dominant craniotubular dysostosis characterized by osteosclerosis, craniofacial dysmorphism, cutis laxa, brachydactyly, and intellectual disability (PMID:26117586).

Heterozygous de novo missense variants in PTDSS1 have been identified in 11 unrelated individuals to date (PMID:38262577), including c.284G>T (p.Arg95Leu), c.829T>C (p.Trp277Arg), and c.1058A>G (p.Gln353Arg) (PMID:25363158, PMID:31403251, PMID:38262577).

Inheritance is autosomal dominant with all reported variants arising de novo; no multiplex familial segregation has been described. These variants are exclusively missense clustering in functionally critical domains with no loss-of-function alleles observed in LMHD probands.

Functional assays demonstrate that LMHD-associated PTDSS1 variants confer gain-of-function, increasing phosphatidylserine synthase activity and leading to elevated PTDS production and urinary phosphoserine over six-fold (PMID:25363158). Attempts to model mutant PTDSS1 in zebrafish were inconclusive due to transgene silencing and incomplete penetrance (PMID:31231513).

In contrast, a heterozygous de novo loss-of-function variant p.Leu137Phe exhibits no catalytic activity and results in developmental delay without osteosclerosis, underscoring a distinct genotype-phenotype mechanism (PMID:35224839).

Collectively, the genetic and experimental concordance accumulated over the past decade establishes a definitive association between PTDSS1 gain-of-function variants and LMHD. PTDSS1 variant analysis should be incorporated into the diagnostic evaluation for individuals with osteosclerotic dysplasia and intellectual disability.

References

• European journal of medical genetics • 2015 • Lenz-Majewski syndrome: Report of a case with novel mutation in PTDSS1 gene PMID:26117586
• Journal of bone and mineral research • 2015 • Lenz-Majewski hyperostotic dwarfism with hyperphosphoserinuria from a novel mutation in PTDSS1 encoding phosphatidylserine synthase 1 PMID:25363158
• European journal of medical genetics • 2024 • Lenz-Majewski syndrome and recurrent otitis media: Are they related or not? PMID:38262577
• American journal of medical genetics. Part A • 2019 • Lenz-Majewski syndrome in a patient from Egypt. PMID:31403251
• F1000Research • 2019 • Analysis of transgenic zebrafish expressing the Lenz-Majewski syndrome gene PTDSS1 in skeletal cell lineages. PMID:31231513
• American journal of medical genetics. Part A • 2022 • De novo loss-of-function variant in PTDSS1 is associated with developmental delay. PMID:35224839

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