Restricted distribution of loss-of-function mutations within theLMX1B genes of nail-patella syndrome patients

Deletion of a branch-point consensus sequence in the LMX1B gene causes exon skipping in a family with nail patella syndrome

“…The syndrome is inherited in an autosomal dominant manner and has been shown to result from mutations in the LIM-homeodomain encoding LMX1B gene. [3][4][5][6] The LMX1B transcription factor plays a role in defining the development of dorsal specific structures during limb development; 7 its role in other organs is unclear. Analysis of over 60 LMX1B mutations in NPS families supports the hypothesis that the syndrome results from haploinsufficiency due to loss of function mutation.…”

“…Analysis of over 60 LMX1B mutations in NPS families supports the hypothesis that the syndrome results from haploinsufficiency due to loss of function mutation. [3][4][5][6] During the search for LMX1B mutations causing NPS, a 17bp deletion was identified upstream of the 3' splice consensus which removed a consensus branchpoint sequence. The effect of this deletion on the splicing of LMX1B RNA was studied further.…”

An Expanding Universe of FSGS Genes and Phenotypes

“…The protein possesses two LIM domains (each with two zinc finger domains involved in protein-protein interactions; e.g., with E47 and LDB1 [NL1 and CLIM2]) at the amino terminus and a homeodomain involved in DNA binding (to a defined FLAT element in gene enhancers) in the middle portion of the molecule. LMX1B mutations associated with nail patella syndrome are clustered in the LIM and DNA binding domains, underscoring the functional importance of these domains (2).…”

“…The pathways that are downstream of LMX1B are complex, including the following genes: (1) genes that control laminin gene expression, at least in the spinal cord (4); (2) podocyte genes with products that include nephrin, podocin (5), CD2AP, and collagen IV chains; (3) Wnt and Pax family genes involved in cell survival; (4) genes involved in 5-hydroxytryptamine synthesis and function; and (5) inflammation-associated genes, including IL-6 and IL-8, leading to NF-kB activation. Although these genes constitute a diverse set of pathways, they suggest the specific ways in which LMX1B may be critical to optimal podocyte function under various physiologic and pathologic situations.…”

“…At present, 164 heterozygous LMX1B mutations are reported to cause nail patella syndrome, which was summarized by Boyer et al (1), and most of these mutations are in the LIM domain or homeodomains (2). The genetic mechanism is very likely haploinsufficiency; indeed, the complete absence of one LMX1B copy has been shown in two cases (9).…”