PIEZO1 – Lymphatic Malformation 6

Piezo-type mechanosensitive ion channel component 1 (PIEZO1) is a large transmembrane protein that mediates mechanotransduction in vascular and lymphatic endothelial cells. Loss-of-function variants in PIEZO1 underlie lymphatic malformation 6 (LMPHM6), an autosomal recessive disorder characterized by nonimmune hydrops fetalis, subcutaneous lymphedema, chylous effusions, and perinatal mortality.

Genetic evidence demonstrates autosomal recessive inheritance with biallelic predicted loss-of-function variants in 7 fetuses and one deceased neonate across 4 unrelated families presenting with isolated nonimmune hydrops fetalis in the second trimester (7 probands)(PMID:36453701). Additional evidence includes two affected siblings with compound heterozygous splicing and missense variants segregating with congenital lymphatic dysplasia (PMID:26387913) and a family with three adverse pregnancies carrying a homozygous missense variant c.5162C>G (p.Ser1721Trp) (PMID:35646098).

The variant spectrum comprises predicted loss-of-function alleles (nonsense, frameshift, splice) and rare missense substitutions, with no recurrent founder variants identified. A representative pathogenic allele is c.5162C>G (p.Ser1721Trp). Segregation analysis in two affected siblings confirms AR transmission (PMID:26387913).

Functional studies reveal that PIEZO1 loss-of-function impairs mechanosensitive channel currents in heterologous systems and patient erythrocytes, while lymphatic endothelial assays show that PIEZO1 knockdown ablates flow‐induced Ca2+ influx and downstream Orai1 signaling, culminating in defective lymphatic sprouting. Lymphatic-specific Piezo1 knockout mice phenocopy human lymphatic dysplasia, and Piezo1 activation restores sprouting (PMID:35701867).

The pathogenic mechanism is bi-allelic loss of PIEZO1 function causing failure of flow-activated lymphangiogenesis, leading to fluid accumulation manifested as pleural effusions and ascites in utero. This mechanistic concordance across cellular, animal, and human studies supports a strong gene–disease relationship.

Key Take-Home: Biallelic PIEZO1 loss-of-function variants cause autosomal recessive lymphatic malformation 6, presenting as nonimmune hydrops fetalis with pleural effusion and ascites, and functional models confirm PIEZO1’s pivotal role in lymphatic mechanotransduction to guide prenatal diagnosis and potential therapeutic targeting.

References

• Clinical genetics • 2023 • Perinatal presentations of non-immune hydrops fetalis due to recessive PIEZO1 disease: A challenging fetal diagnosis. PMID:36453701
• Nature communications • 2015 • Impaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia. PMID:26387913
• Frontiers in genetics • 2022 • A Novel Homozygous Missense Mutation of PIEZO1 Leading to Lymphatic Malformation-6 Identified in a Family With Three Adverse Pregnancy Outcomes due to Nonimmune Fetal Hydrops. PMID:35646098
• Circulation research • 2022 • Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion. PMID:35701867

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