LAMB2 – Familial Nephrotic Syndrome

LAMB2 encodes laminin β2, a key basement membrane protein expressed in glomerular basement membranes and ocular tissues. Biallelic LAMB2 variants cause autosomal recessive familial nephrotic syndrome, often overlapping Pierson syndrome with congenital nephrotic syndrome and ocular anomalies such as microcoria. Genetic testing for LAMB2 is indicated in infants presenting with early-onset nephrotic syndrome, particularly when ocular or extrarenal features are present.

1. Clinical Validity and Inheritance

Multiple unrelated families (n = 5) have been reported with homozygous or compound heterozygous LAMB2 variants in patients presenting with congenital nephrotic syndrome ([PMID:15367484]). In a consanguineous kindred, two affected siblings segregated a novel missense variant, confirming autosomal recessive inheritance and intrafamilial segregation ([PMID:16912710]). Across case series and cohort studies, at least 10 probands have been described with LAMB2-associated familial nephrotic syndrome, supporting a Definitive gene–disease relationship.

2. Genetic Evidence

Inheritance is autosomal recessive. Segregation analyses document affected sib recurrence in consanguineous families (2 affected relatives) and compound heterozygosity in nonconsanguineous kindreds. Reported variants include truncating alleles (e.g., c.767del, p.Gly256fs; c.2848C>T, p.Gln950Ter) and missense changes clustering in the LN domain (e.g., c.737G>A (p.Arg246Gln)) ([PMID:15367484], [PMID:16912710]). In total, 10 probands with 18 LAMB2 alleles have been described, meeting ClinGen Strong genetic evidence thresholds.

3. Functional Evidence

Immunohistochemistry and Western blot demonstrate complete loss of laminin β2 in patient kidney biopsies with truncating variants, confirming absence of protein expression ([PMID:15367484]). Lamb2 knockout mice recapitulate congenital nephrosis and ocular defects. Transgenic mice expressing the hypomorphic R246Q allele show dose-dependent proteinuria and basement membrane defects, implicating impaired laminin secretion as pathogenic ([PMID:21511833]). These concordant in vivo and in vitro data provide Moderate functional evidence.

4. Conflicting Evidence

Missense LN-domain variants such as p.Arg246Gln may present with milder renal phenotypes and minimal extrarenal features, indicating variable expressivity but not refuting the overall gene–disease relationship.

5. Integration and Clinical Utility

LAMB2 loss-of-function and hypomorphic alleles result in insufficient laminin β2 incorporation into the GBM, causing congenital proteinuria and rapid progression to renal failure. Genetic confirmation enables tailored management, early renal replacement planning, and family counseling. LAMB2 sequencing should be part of diagnostic panels for familial and congenital nephrotic syndrome, especially when ocular anomalies are observed.

Key Take-home: Biallelic LAMB2 variants definitively cause autosomal recessive familial nephrotic syndrome; comprehensive LAMB2 testing is critical for early diagnosis and management.

References

• Human molecular genetics • 2004 • Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities PMID:15367484
• Kidney international • 2006 • Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2-associated disorders PMID:16912710
• Journal of the American Society of Nephrology • 2011 • A missense LAMB2 mutation causes congenital nephrotic syndrome by impairing laminin secretion PMID:21511833
• Journal of medical genetics • 2009 • Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome PMID:19251977

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