c.194 A>C (Q65P) mutation in the LMX1B gene in patients with nail-patella syndrome associated with glaucoma

PURPOSE: To report the clinical, ophthalmic, extraophthalmic, and genetic characteristics of nail-patella syndrome (NPS) in a Chilean family and to investigate the expressivity of open angle glaucoma (OAG) and ocular hypertension (OHT) in the family members. METHODS: Five family members affected with NPS and two unaffected members underwent a complete ophthalmologic examination, including computerized visual field, optical coherence tomography (OCT) of the optic disc and ultrasound pachymetry. Renal function was assessed by urinalysis and blood tests. Orthopedic evaluations were also performed, including radiological studies of the wrist, elbow and hip joints. Genomic DNA was extracted from peripheral leukocytes of the five affected and two unaffected family members. Exons 2–6 of the LIM homeobox transcription factor 1-beta (LMX1B) gene were screened for mutations by DNA sequencing of the proband. We also screened for mutations in exon 2 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) of the other participants and 91 blood donors. RESULTS: Five living family members from three generations were positively diagnosed with NPS, three of them with varying degrees of OAG and one with OHT. Retinal nerve fiber layer (RNFL) thickness measured by spectral domain OCT was below normal values in three individuals. All subjects evaluated had normal nephrologic function. Orthopedic, clinical, and radiological alterations were compatible with NPS. Screening for mutations in exons 2- 6 of LMX1B showed a heterozygous missense mutation c.194 A>C changing glutamine to proline within exon 2 in codon 65 (Q65P) of the coding sequence. This mutation was present in all NPS subjects and absent in the unaffected family members and in 91 Chilean blood donors. CONCLUSIONS: This is the first report of c.194 A>C mutation in LMX1B in a Chilean family with NPS and the second worldwide. The phenotype associated with this mutation is variable within the family, although we noted a close connection between the presence of the c.194 A>C mutation and the presence of OHT or OAG and probably also with an early onset of OHT in patients with NPS. All subjects older than 21 years had either OHT or OAG. We also suggest that the LMX1B mutation may be related to affective disorders.