Abstract
BackgroundNail-patella syndrome (NPS) is an autosomal dominant developmental disorder most commonly characterized by dyplasia of nail or patella, the radial head or the humeral head hypoplasia, and, frequently ocular abnormalities and renal disease. It is caused by heterozygous loss-of-function mutations in the LMX1B gene, which encodes LIM homeodomain transcription factor and is essential for regulating the dorsal limb fate.MethodsA five generation pedigree was recruited. Genomic DNA was extracted from the peripheral blood samples. Mutation detection was performed by Sanger sequencing the LMX1B gene. In silico functional annotation of the variant was performed using the in silico predictors SIFT, PolyPhen-2 and Mutation Taster.ResultsA novel heterozygous small deletion within exon 4 of LMX1B, c.712_714delTTC, was identified in a rare five-generation NPS pedigree. The mutation resulted in a deletion of the conserved amino acid phenylalanine at codon 238 (p.Phe238del), which located in the homeodomain of LMX1B may abolish DNA binding with the molecule. Conformational prediction showed that the variation could transform the helical structure comprising p.Phe234, p.Lys235, p.Ala236, and p.Ser237.ConclusionWe identified a novel NPS-causing LMX1B mutation and expanded the spectrum of mutations in the LMX1B gene. The c.712_714delTTC mutation may affect the quaternary structure of LMX1B, which is essential for the specification of dorsal limb fate at both zeugopodal and autopodal levels, leading to typical NPS.
Highlights
Nail-patella syndrome (NPS) is an autosomal dominant developmental disorder most commonly characterized by dyplasia of nail or patella, the radial head or the humeral head hypoplasia, and, frequently ocular abnormalities and renal disease
Epidemiological studies have suggested that about 30– 40% of patients with NPS develop a renal disease and open-angle glaucoma has been identified as a feature of the syndrome in some patients [2, 3]
Heterozygous loss-of-function mutations of LIM homeobox transcription factor 1-beta (LMX1B) (LIM homeobox transcription factor 1, beta, NM_002316.3), a gene located on 9q33.3, have been widely accepted as the major pathogenic mechanism behind NPS
Summary
Nail-patella syndrome (NPS) is an autosomal dominant developmental disorder most commonly characterized by dyplasia of nail or patella, the radial head or the humeral head hypoplasia, and, frequently ocular abnormalities and renal disease. It is caused by heterozygous loss-of-function mutations in the LMX1B gene, which encodes LIM homeodomain transcription factor and is essential for regulating the dorsal limb fate. Nail–patella syndrome (NPS, OMIM #161200) is a rare autosomal dominant disorder with an incidence of approximately 1 in 50,000 live births, involving the maldevelopment of elbow joints, nail hypoplasia, and absent or hypoplastic patellae [1] It warrants particular attention because those affected progress to variable degrees of physical dysfunction involving different organs.
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