Genotype-phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy.

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Publication year
2005Source
European Journal of Human Genetics, 13, 8, (2005), pp. 935-946ISSN
Publication type
Article / Letter to editor

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Organization
Human Genetics
Nephrology
Paediatrics
Radiology
Otorhinolaryngology
Ophthalmology
Medical Psychology
Health Evidence
Orthopaedics
Former Organization
Epidemiology, Biostatistics & HTA
Journal title
European Journal of Human Genetics
Volume
vol. 13
Issue
iss. 8
Page start
p. 935
Page end
p. 946
Subject
DCN 1: Perception and Action; DCN 2: Functional Neurogenomics; EBP 1: Determinants of Health and Disease; EBP 2: Effective Hospital Care; IGMD 3: Genomic disorders and inherited multi-system disorders; IGMD 5: Health aging / healthy living; IGMD 9: Renal disorder; NCEBP 10: Human Movement & Fatigue; NCEBP 2: Evaluation of complex medical interventions; NCEBP 8: Psychological determinants of chronic illness; NCMLS 5: Membrane transport and intracellular motility; NCMLS 6: Genetics and epigenetic pathways of disease; ONCOL 1: Hereditary cancer and cancer-related syndromes; ONCOL 2: Age-related aspects of cancer; ONCOL 4: Quality of Care; UMCN 1.1: Functional Imaging; UMCN 1.5: Interventional oncology; UMCN 3.3: Neurosensory disorders; UMCN 4.3: Tissue engineering and reconstructive surgery; UMCN 5.4: Renal disorders; EBP 1: Determinants of Health and Disease; EBP 2: Effective Hospital Care; NCEBP 10: Human Movement & FatigueAbstract
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.
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- Academic publications [202923]
- Electronic publications [101091]
- Faculty of Medical Sciences [80072]
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