LMX1B – Nail-Patella-like Renal Disease

LMX1B, encoding a LIM-homeodomain transcription factor, is associated with nail-patella-like renal disease, a renal-limited form of Nail-Patella Syndrome characterized by glomerulopathy without skeletal or nail abnormalities. Heterozygous variants in LMX1B lead to isolated podocyte defects manifesting as microscopic hematuria and proteinuria in early life. The disease is catalogued as nail-patella-like renal disease and the gene as LMX1B.

XLINKInheritance and Genetic Evidence: Nail-patella-like renal disease follows an autosomal dominant inheritance pattern with heterozygous LMX1B mutations. Four unrelated probands have been reported: a 6-year-old girl with hematuria and GBM abnormalities ([PMID:24042019]), a family misdiagnosed as Fabry disease ([PMID:32791958]), and two additional families sharing the recurrent R246Q variant ([PMID:28059119]). In all cases, the LMX1B c.737G>A (p.Arg246Gln) variant segregated with disease in three kindreds, supporting pathogenicity.

Segregation and Case Series: Segregation analysis revealed co-segregation of the c.737G>A (p.Arg246Gln) variant with renal phenotypes in three families, encompassing at least three additional affected relatives. Clinical features include early microscopic hematuria (HP:0002907), mild to nephrotic-range proteinuria (HP:0012595), and focal segmental glomerulosclerosis (HP:0000097).

Functional Characterization: Luciferase reporter assays in patient-derived podocytes demonstrated partial but significant reduction of LMX1B transcriptional activity for R246Q without dominant-negative interference, indicating haploinsufficiency ([PMID:24042019]). Cell-based studies using myc-LMX1BR246Q overexpression revealed aberrant CD2AP expression and downregulation of WT1(-KTS) isoforms, suggesting disruption of podocyte gene networks and glomerular filtration barrier integrity ([PMID:28059119]).

Mechanism of Pathogenicity: The R246Q substitution within the homeodomain diminishes DNA binding, leading to haploinsufficiency and dominant-negative effects on downstream targets (NPHS1, GLEPP1, WT1). These molecular perturbations mirror those in Nail-Patella Syndrome nephropathy but spare extrarenal structures due to residual LMX1B activity.

Clinical Integration: The recurrent c.737G>A (p.Arg246Gln) variant in LMX1B meets moderate ClinGen criteria for pathogenicity, with multiple families, segregation, and concordant functional data. Genetic testing for LMX1B should be considered in patients with familial isolated glomerulopathy. Early molecular diagnosis enables surveillance for renal progression and informs family screening.

Key Take-home: LMX1B haploinsufficiency due to c.737G>A (p.Arg246Gln) is a validated cause of autosomal dominant nail-patella-like renal disease, supporting its inclusion in nephropathy gene panels for early diagnosis and management.

References

• Nephrology, Dialysis, Transplantation • 2014 • LMX1B mutation with residual transcriptional activity as a cause of isolated glomerulopathy. PMID:24042019
• BMC Nephrology • 2020 • Nail-patella-like renal disease masquerading as Fabry disease on kidney biopsy: a case report. PMID:32791958
• Scientific Reports • 2017 • Dysregulation of WTI (-KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation. PMID:28059119

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