title: Genotype-phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy.
abstract: Nail-patella syndrome (NPS) is characterized by developmental defects of dorsal limb structures, nephropathy, and glaucoma and is caused by heterozygous mutations in the LIM homeodomain transcription factor LMX1B. In order to identify possible genotype-phenotype correlations, we performed LMX1B mutation analysis and comprehensive investigations of limb, renal, ocular, and audiological characteristics in 106 subjects from 32 NPS families. Remarkable phenotypic variability at the individual, intrafamilial, and interfamilial level was observed for different NPS manifestations. Quantitative urinanalysis revealed proteinuria in 21.3% of individuals. Microalbuminuria was detected in 21.7% of subjects without overt proteinuria. Interestingly, nephropathy appeared significantly more frequent in females. A significant association was established between the presence of clinically relevant renal involvement in an NPS patient and a positive family history of nephropathy. We identified normal-tension glaucoma (NTG) and sensorineural hearing impairment as new symptoms associated with NPS. Sequencing of LMX1B revealed 18 different mutations, including six novel variants, in 28 families. Individuals with an LMX1B mutation located in the homeodomain showed significantly more frequent and higher values of proteinuria compared to subjects carrying mutations in the LIM domains. No clear genotype-phenotype association was apparent for extrarenal manifestations. This is the first study indicating that family history of nephropathy and mutation location might be important in precipitating individual risks for developing NPS renal disease. We suggest that the NPS phenotype is broader than previously described and that NTG and hearing impairment are part of NPS. Further studies on modifier factors are needed to understand the mechanisms underlying phenotypic heterogeneity.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, The Netherlands. t.g.j.derks@bkk.umcg.nl
authors.forename: Ernie M H F
authors.initials: EM
authors.lastname: Bongers
authors.forename: Frans T
authors.initials: FT
authors.lastname: Huysmans
authors.forename: Elena
authors.initials: E
authors.lastname: Levtchenko
authors.forename: Jacky W
authors.initials: JW
authors.lastname: de Rooy
authors.forename: Johan G
authors.initials: JG
authors.lastname: Blickman
authors.forename: Ronald J C
authors.initials: RJ
authors.lastname: Admiraal
authors.forename: Patrick L M
authors.initials: PL
authors.lastname: Huygen
authors.forename: Johannes R M
authors.initials: JR
authors.lastname: Cruysberg
authors.forename: Pauline A M P
authors.initials: PA
authors.lastname: Toolens
authors.forename: Judith B
authors.initials: JB
authors.lastname: Prins
authors.forename: Paul F M
authors.initials: PF
authors.lastname: Krabbe
authors.forename: George F
authors.initials: GF
authors.lastname: Borm
authors.forename: Jeroen
authors.initials: J
authors.lastname: Schoots
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Angela M F
authors.initials: AM
authors.lastname: van Remortele
authors.forename: Lies H
authors.initials: LH
authors.lastname: Hoefsloot
authors.forename: Albert
authors.initials: A
authors.lastname: van Kampen
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
mesh_terms: D000293:Adolescent; D000328:Adult; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007674:Kidney Diseases / Q000150:complications* / Q000235:genetics; D060850:LIM-Homeodomain Proteins; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009261:Nail-Patella Syndrome / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors