LAMB2 – Pierson syndrome

Pierson syndrome is an autosomal recessive oculorenal disorder caused by biallelic mutations in the LAMB2 gene (HGNC:6487), which encodes the laminin β2 chain integral to the glomerular basement membrane and ocular basement membranes. Affected individuals present with congenital nephrotic syndrome (HP:0008677), early-onset renal insufficiency (HP:0000083), and characteristic ocular anomalies such as microcoria (HP:0000616). Genetic testing of LAMB2 should be included in the diagnostic evaluation of infants with steroid-resistant or congenital nephrotic syndrome, especially when accompanied by ocular findings.

The inheritance pattern of LAMB2-related Pierson syndrome is autosomal recessive, with over 110 patients reported across 39 unrelated families, demonstrating consistent segregation of truncating and missense variants in affected kindreds (PMID:20556798). Multi-family linkage and homozygosity mapping localized pathogenic alleles to LAMB2, and sequencing revealed both null and hypomorphic variants that correlate with phenotypic variability.

Case series and founder studies have delineated a broad variant spectrum, including missense, nonsense, frameshift, and splice-site mutations. Notably, the variant c.440A>G (p.His147Arg) was identified homozygous in an extended consanguineous Mennonite pedigree of nine living affected individuals, all manifesting chronic kidney disease and chorioretinal changes without microcoria (PMID:21236492).

Mechanistic studies in Lamb2−/− mice recapitulate the human phenotype, exhibiting congenital nephrosis, mesangial sclerosis, and ocular muscle hypoplasia. Immunohistochemistry and Western blotting confirm the absence of laminin β2 in patient tissues and animal models, establishing loss of function as the pathogenic mechanism (PMID:15367484).

No reproducible conflicting evidence has been reported to dispute the LAMB2–Pierson syndrome association. Genotype-phenotype correlations reveal that truncating alleles often lead to severe neonatal onset disease, whereas missense or in-frame variants may result in milder or isolated nephropathy without extrarenal involvement.

In summary, robust genetic and experimental data support a Strong association between LAMB2 and Pierson syndrome. Clinical testing for LAMB2 variants enables early diagnosis, informs prognosis, and guides management decisions, including renal replacement planning and ophthalmologic surveillance.

References

• Human Molecular Genetics • 2004 • Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities PMID:15367484
• Ophthalmology • 2011 • A novel mutation of LAMB2 in a multigenerational mennonite family reveals a new phenotypic variant of Pierson syndrome PMID:21236492
• Human Mutation • 2010 • Mutations in the human laminin beta2 (LAMB2) gene and the associated phenotypic spectrum PMID:20556798

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