Novel LMX1B mutation in familial nail-patella syndrome with variable expression of open angle glaucoma

Abstract

Purpose: To describe the genetic and clinical findings in a large Spanish pedigree with nail-patella syndrome (NPS) and to investigate the expressivity of open angle glaucoma (OAG) in the family members.

Methods: All individuals underwent a complete ophthalmologic examination, including optical coherence tomography (OCT) of the optic disc and peripapillary region and ultrasound pachymetry. Screening for mutations in the LMX1B gene was performed by denaturing gradient gel electrophoresis and direct genomic sequencing analysis.

Results: Ten family members had NPS, seven with varying degrees of ocular hypertension (OHT). Only one of these had advanced OAG. The others showed high pachymetry values and OCT retinal nerve fiber layer (RNFL) thickness above the normal values. Screening for mutations in the exonic and flanking sequences of the LMX1B gene showed a deletion of one G (289delG) within the coding sequence of exon 3 at codon 97, resulting in a frame shift that creates a premature stop at codon 105 (E97fsX105), predicting a truncated protein. This mutation was present in all NPS patients and absent in the unaffected family members.

Conclusions: A novel mutation in the homeobox transcription factor LMX1B causes NPS in a family with variable expressivity of the syndrome, including OAG. The pathogenic mechanism resulting from the mutation is presumably haploinsufficiency rather than a dominant negative effect, which would explain the clinical variability in this family. All NPS OHT patients had considerably thick corneas and RNFL.

Figure 1

Genetic results of the NPS family. A: Pedigree of a Spanish family with nail-patella syndrome (NPS). Filled squares and circles denote NPS-affected males and females, respectively. Open squares and circles represent males and females without NPS. A diagonal line through the symbols marks a deceased individual. An arrow indicates the index patient (VI-4). The following symbols were used: wild-type allele (+)2889delG allele (-), and 372A>G allele (x), correspond to a, and allele, respectively. B: Denaturing gradient gel electrophoresis (DGGE) of the PCR fragment of exon 3. The different electrophoretic profiles correspond to carriers of the following: 289delG/WT (IV-1, IV-2, IV-3, V-1, V-2, V-6, and VI-2); WT/372A>G (V-3, VI-1, VI-6, VI-7); 289delG/372A gt G (V-5, V-9, VI-4); WT/WT (V-4, V-8, VI-3) and 372A>G/372A>G (VI-5). WT=wild type. C: DNA genomic sequencing of exon 3 of LMX1B showing the 289delG mutation (left) and a control DNA (right).

Figure 2

Gonioscopy of NPS patients. A: Color photograph taken during gonioscopy of multiple iris processes in patient V-6. B: Color photograph of a highly pigmented anterior chamber angle of patient V-9.

Figure 3

Optical coherence tomography of patients IV-2 and V-1. A: Optical coherence tomography (OCT) diagram for patient IV-2 in which above-normal retinal nerve fiber layer (RNFL) thickness measurements are expressed in white in the pie chart. Green sectors are within the normal range. B: OCT Fast optic nerve head protocol of patient V-1, confirming cup enlargement.