LMX1B – Nail-patella Syndrome

LMX1B encodes a LIM homeodomain transcription factor critical for dorsal limb, kidney and ocular development. Heterozygous loss-of-function variants in LMX1B cause autosomal dominant Nail-patella syndrome, a pleiotropic disorder characterised by nail dysplasia, hypoplastic or absent patellae, iliac horns and variable nephropathy.

Multiple genetic studies have identified 25 distinct LMX1B mutations across 37 unrelated families with co-segregation of the classic NPS phenotype (PMID:9837817). Inheritance is autosomal dominant with full penetrance of limb anomalies and 20–60% of individuals developing proteinuria or renal failure. Segregation has been documented in multiple multigenerational pedigrees, including mother, sister, and two daughters in a Taiwanese family (PMID:12645195) and five affected members across three generations in a Korean kindred (PMID:19721866).

The variant spectrum includes missense, nonsense, splice-site and frameshift mutations clustering within LIM and homeodomains, as well as whole-gene deletions. A recurrent truncating allele, c.661C>T (p.Arg221Ter), exemplifies the loss-of-function mechanism (PMID:24720768). Microdeletions spanning LMX1B confirm haploinsufficiency as the principal pathogenic mechanism (PMID:18414507).

Functional concordance is supported by Lmx1b-null mice, which phenocopy nail absence, patellar aplasia and renal dysplasia seen in human NPS (PMID:9590287). Inducible podocyte-specific Lmx1b knockout in adult mice induces proteinuria and cytoskeletal defects, demonstrating a critical role in glomerular filtration barrier maintenance (PMID:23990680). Biochemical assays of the truncated R198X mutant reveal disrupted nuclear localization and altered transactivation, consistent with haploinsufficiency (PMID:24720768).

Integration of genetic and experimental data yields a Definitive association between LMX1B and Nail-patella syndrome. The extensive mutation spectrum, robust co-segregation in pedigrees and concordant animal and cell models support diagnostic genetic testing, family screening and mechanistic studies. Key Take-home: Heterozygous LMX1B variants are definitively linked to Nail-patella syndrome; molecular diagnosis guides clinical management and surveillance.

References

• American journal of human genetics • 1998 • Mutation analysis of LMX1B gene in nail-patella syndrome patients. PMID:9837817
• Nature genetics • 1998 • Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. PMID:9590287
• Journal of the Formosan Medical Association = Taiwan yi zhi • 2002 • Nail-patella syndrome with renal involvement and antecubital pterygia. PMID:12645195
• The Korean journal of internal medicine • 2009 • A synonymous genetic alteration of LMX1B in a family with nail-patella syndrome. PMID:19721866
• The British journal of dermatology • 2014 • Biochemical properties of the recurrent LMX1b truncated mutant carried in a Taiwanese family with nail-patella syndrome. PMID:24720768
• European journal of human genetics : EJHG • 2008 • Identification of entire LMX1B gene deletions in nail patella syndrome: evidence for haploinsufficiency as the main pathogenic mechanism underlying dominant inheritance in man. PMID:18414507
• Journal of the American Society of Nephrology : JASN • 2013 • LMX1B is essential for the maintenance of differentiated podocytes in adult kidneys. PMID:23990680

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