LRP2 – Donnai-Barrow Syndrome

Donnai-Barrow syndrome (DBS) is a rare autosomal recessive multisystem disorder characterized by craniofacial dysmorphism, agenesis of the corpus callosum, sensorineural hearing loss, congenital diaphragmatic hernia, omphalocele, high-grade myopia, and proteinuria (PMID:19577669, PMID:17632512). DBS results from biallelic pathogenic variants in LRP2 (HGNC:6694), which encodes the multiligand endocytic receptor megalin expressed in neuroepithelium, renal proximal tubules, and sensory epithelia.

Genetic studies have identified at least 27 distinct LRP2 variants—including nonsense, frameshift, canonical splice-site, and rare missense changes—in more than 50 unrelated probands from over 10 families, confirming autosomal recessive inheritance (PMID:17632512, PMID:31821692). A recurrent homozygous frameshift variant c.6978dupG (p.Thr2327AspfsTer4) was detected prenatally in consanguineous parents after ultrasound diagnosis of diaphragmatic hernia and corpus callosum agenesis, solidifying loss-of-function as the primary mechanism (PMID:31821692).

Segregation analysis across seven multiplex pedigrees demonstrated consistent co-segregation of biallelic LRP2 variants with DBS phenotypes in 19 additional affected relatives, providing robust pedigree support for pathogenicity (PMID:17632512).

Functional assays using patient-derived induced pluripotent stem cell-derived neuroepithelial and renal proximal tubule models have shown that the common missense mutation p.Arg3192Gln leads to ligand-induced receptor decay and lysosomal depletion of megalin, reproducing the resorption defects seen in DBS kidneys (PMID:32471643). Animal models, including mouse and zebrafish loss-of-function studies, recapitulate neural tube closure defects and ocular enlargement, underscoring megalin haploinsufficiency as the pathogenic mechanism.

No conflicting evidence disputing the LRP2–DBS association has been reported. Variants across diverse populations yield consistent clinical phenotypes and functional impacts, supporting a unified disease mechanism.

In summary, definitive clinical, genetic, and experimental data establish LRP2 as the causal gene for DBS, enabling precise molecular diagnosis, carrier screening, and informing future therapeutic strategies.

References

• European Journal of Medical Genetics • 2009 • A 56-year-old female patient with facio-oculo-acoustico-renal syndrome (FOAR) syndrome. Report on the natural history and of a novel mutation. PMID:19577669
• Nature Genetics • 2007 • Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. PMID:17632512
• American Journal of Medical Genetics Part A • 2020 • A prenatally diagnosed case of Donnai-Barrow syndrome: Highlighting the importance of whole exome sequencing in cases of consanguinity. PMID:31821692
• Kidney International • 2020 • Induced pluripotent stem cell-based disease modeling identifies ligand-induced decay of megalin as a cause of Donnai-Barrow syndrome. PMID:32471643

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