Molecular cytogenetic detection of 9q34 breakpoints associated with nail patella syndrome

Silahtaroglu, Asli; Hol, F.A.; Jensen, Peter K.A.; Erdel, Martin; Duba, Hans-Christoph; Geurds, M.P.A.; Knoers, Nine V A M; Mariman, E.C.M.; Tümer, Zeynep; Utermann, Gerd; Wirth, Jutta; Bugge, Merete; Tommerup, Niels

doi:10.1038/sj.ejhg.5200260

Cited by 17 publications

(13 citation statements)

References 26 publications

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“…In addition, a 17 bp intronic deletion was detected in one NPS family and balanced translocations, presumably disrupting LMX1B have been reported. 11,12 Linkage studies in NPS families did not reveal evidence for locus heterogeneity thus far. Molecular studies in Lmx1b null mice modelling the NPS phenotype have proven to be pivotal to our understanding of the role of Lmx1b in the normal and disrupted development of dorsal limb structures, the kidney, the eye, and the central nervous system, and particularly focussed on the pathogenesis underlying glomerulopathy in the past decade.…”

Section: Introductionmentioning

confidence: 99%

Identification of entire LMX1B gene deletions in nail patella syndrome: evidence for haploinsufficiency as the main pathogenic mechanism underlying dominant inheritance in man

et al. 2008

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Heterozygous mutations in the LMX1B gene cause nail patella syndrome (NPS) that is associated with nail and skeletal malformations, nephropathy, and glaucoma. Previous phenotype studies of Lmx1b null mice revealed dorsal limb and renal anomalies similar to human NPS, which contributed to the identification of heterozygous mutations in this LIM-homeodomain protein LMX1B as the genetic defect responsible for NPS. Despite advanced insight into the role of the Lmx1b transcription factor in a broad range of animal developmental programs, the pathogenic mechanism underlying dominant inheritance of NPS in man remained unclear. Here, we describe for the first time the detection of two entire LMX1B gene deletions and one smaller exonic LMX1B deletion by multiplex ligation-dependent probe amplification (MLPA) in a series of eight unrelated families with classical features of NPS in whom no pathogenic LMX1B mutation was found by sequence analysis. The identification of entire LMX1B deletions strongly confirms that haploinsufficiency is the principal pathogenetic mechanism of NPS and suggests a difference in dosage sensitivity for this gene between mice and man.

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Section: Introductionmentioning

confidence: 99%

Identification of entire LMX1B gene deletions in nail patella syndrome: evidence for haploinsufficiency as the main pathogenic mechanism underlying dominant inheritance in man

et al. 2008

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“…For FISH analysis, biotin labelled PAC clones 830-M14 and 1195-M2 located in the LMX1B region were used according to standard procedures. 32 Statistics Clinical and molecular findings were analysed using linear and logistic regression models. Since age and gender are known covariates in developing renal, ocular, audiological, and psychological anomalies, multivariate analysis of these symptoms was adjusted for age and gender.…”

Section: Mutational and Fish Analysismentioning

confidence: 99%

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

et al. 2005

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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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“…Their karyotypes were: 46,XY,inv(1)(p36q21); 46,XY,inv(1)(q21.2q42); 46,XY,t (1;16)(q21;p11); and 46,XY,t(1;4)(q21;q33)mat. Fluorescence in situ hybridisation (FISH) was carried out using standard procedures 14 and the bacterial artificial chromosome (BAC) clones were obtained from the MCN Reference Centre at the Max Planck-Institute for Molecular Genetics, Berlin (http://www.molgen.mpg.de/~cytogen/). AZFa, AZFb, AZFc and AZFd deletions were screened for by 11 STS markers (SY84, SY95, SY113, SY117, SY121, SY129, SY145, SY242, SY239, SY208 and SY255) 15 .…”

Section: Cytogenetic and Molecular Analyses Of Cases With Karyotypes mentioning

confidence: 99%

An excess of chromosome 1 breakpoints in male infertility

et al. 2004

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3 -48 Full affiliations can be seen as electronic supplementIn a search for potential infertility loci, which might be revealed by clustering of chromosomal breakpoints, we compiled 464 infertile males with a balanced rearrangement from Mendelian Cytogenetics Network database (MCNdb) and compared their karyotypes with those of a Danish nation-wide cohort. We excluded Robertsonian translocations, rearrangements involving sex chromosomes and common variants. We identified 10 autosomal bands, five of which were on chromosome 1, with a large excess of breakpoints in the infertility group. Some of these could potentially harbour a male-specific infertility locus. However, a general excess of breakpoints almost everywhere on chromosome 1 was observed among the infertile males: 26.5 versus 14.5% in the cohort. This excess was observed both for translocation and inversion carriers, especially pericentric inversions, both for published and unpublished cases, and was significantly associated with azoospermia. The largest number of breakpoints was reported in 1q21; FISH mapping of four of these breakpoints revealed that they did not involve the same region at the molecular level. We suggest that chromosome 1 harbours a critical domain whose integrity is essential for male fertility.

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Molecular cytogenetic detection of 9q34 breakpoints associated with nail patella syndrome

Cited by 17 publications

References 26 publications

Identification of entire LMX1B gene deletions in nail patella syndrome: evidence for haploinsufficiency as the main pathogenic mechanism underlying dominant inheritance in man

Identification of entire LMX1B gene deletions in nail patella syndrome: evidence for haploinsufficiency as the main pathogenic mechanism underlying dominant inheritance in man

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

An excess of chromosome 1 breakpoints in male infertility

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