A spectrum of LMX1B mutations in Nail-Patella syndrome: New point mutations, deletion, and evidence of mosaicism in unaffected parents

Abstract

Purpose: Nail-Patella syndrome (MIM 161200) is a rare autosomal dominant disorder characterized by hypoplastic or absent patellae, dystrophic nails, dysplasia of the elbows, and iliac horn. In 40% of cases, a glomerular defect is present and, less frequently, ocular damage is observed. Inter-and intrafamilial variable expressivity of the clinical phenotype is a common finding. Mutations in the human LMX1B gene have been demonstrated to be responsible for Nail-Patella syndrome in around 80% of cases. Methods: Standard polymerase chain reaction and sequencing methods were used for mutation and single nucleotide polymorphism identification and control of cloned sequences. Array-CGH (Agilent, 244A Kit) was used for detection of deletions. Standard cloning techniques and the Snapshot method were used for analysis of mosaicism. Results: In this study, we present the results of LMX1B screening of 20 Nail-Patella syndrome patients. The molecular defect was found in 17 patients. We report five novel mutations and a ϳ2 Mb deletion in chromosome 9q encompassing the entire LMX1B gene in a patient with a complex phenotype. We present evidence of somatic mosaicism in unaffected parents in two cases, which, to our knowledge, are the first reported cases of inheritance of a mutated LMX1B allele in Nail-Patella syndrome patients from a mosaic parent. Conclusion: The study of the described case series provides some original observations in an "old" genetic disorder. Genet Med 2010:12(7):431-439.

LMX1B Mutations Cause Hereditary FSGS without Extrarenal Involvement

“…11,16,27,28 They cause Seventeen regions of interest spanning 118 Mb were identified on chromosomes 1, 2, 3, 4, 6, 9, 11, 15, 17, and 19 (with a maximum Lod score of 1.2). One 8.9-Mb region on chromosome 9, indicated here by an arrow, contains the LMX1B locus.…”

An Expanding Universe of FSGS Genes and Phenotypes

“…Recently, a family was reported in which parental somatic mosaicism was noted; thus, some tissues, including presumably germ cells, have the mutated allele, but other tissues do not. This finding would explain the de novo appearance of nail patella syndrome in a family and some cases of intrafamilial heterogeneity (10).…”

“…IRI induces rapid swelling and fragmentation of mitochondria in the PT, 8 leading to sustained energetic deficits 9 and activation of cell death pathways. 10 Increased mitochondrial ROS production is thought to be a major mechanism in the pathogenesis of IRI, particularly during reperfusion when O 2 is represented to damaged OXPHOS complexes. 11 Nonspecific antioxidants have proven disappointing as a therapy in AKI, perhaps partly because of the realization that nonmitochondrial ROS have important physiologic signaling roles in the kidney.…”

LIM homeobox transcription factor 1B expression affects renal interstitial fibrosis and apoptosis in unilateral ureteral obstructed rats

“…Most prominently, a large number of mutations in the Lmx1b gene have been described for nail-patella syndrome (NPS; MIM 161200) (3,7,25,30,31,34), also called hereditary osteoonychodysplasia. This is a rare autosomal dominant disease that is characterized by developmental defects in the dorsal limb structures, e.g., absent or small patellae, pelvis iliac horn malformation, and absent or hypoplastic nails (7).…”

“…rior segment of the eye, and dopaminergic and serotonergic neurons (7,8,25), and is commonly expressed in vertebrate embryos during early embryonic development.…”