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A deletion variant in LMX1B causing nail-patella syndrome in Japanese twins.

ABSTRACT: Nail-patella syndrome (NPS) is a hereditary disease caused by pathogenic variants in LMX1B and characterized by nail, limb, and renal symptoms. This study revealed a likely pathogenic LMX1B variant, NM_002316.4: c.723_726delinsC (p.Ser242del), in Japanese twins with clubfoot. The patients' mother, who shared this variant, developed proteinuria after delivery. p.Ser242del is located in the homeodomain of the protein, in which variants that cause renal disease tend to cluster. Our findings highlight p.Ser242del as a likely pathogenic variant, expanding our knowledge of NPS.

SUBMITTER: Kishio N

PROVIDER: S-EPMC10904864 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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A deletion variant in LMX1B causing nail-patella syndrome in Japanese twins.

Kishio Nozomu N Iwama Kazuhiro K Nakanishi Sayuri S Shindo Ryosuke R Yasui Masaki M Nicho Naoki N Takahashi Atsushi A Kohara Mana M Hirata Michisato M Kemmotsu Takahiro T Tanoshima Miki M Ito Shuichi S

Human genome variation 20240229 1

Nail-patella syndrome (NPS) is a hereditary disease caused by pathogenic variants in LMX1B and characterized by nail, limb, and renal symptoms. This study revealed a likely pathogenic LMX1B variant, NM_002316.4: c.723_726delinsC (p.Ser242del), in Japanese twins with clubfoot. The patients' mother, who shared this variant, developed proteinuria after delivery. p.Ser242del is located in the homeodomain of the protein, in which variants that cause renal disease tend to cluster. Our findings highlig ...[more]

PMID: 38424113

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A novel small deletion of LMX1B in a large Chinese family with nail-patella syndrome.

Project description: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.

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Paroxysmal Cranial Dyskinesia and Nail-Patella Syndrome Caused by a Novel Variant in the LMX1B Gene.

Project description:BackgroundIn a Danish family, multiple individuals in five generations present with early-onset paroxysmal cranial dyskinesia, musculoskeletal abnormalities, and kidney dysfunction.ObjectiveTo demonstrate linkage and to identify the underlying genetic cause of disease.MethodsGenome-wide single-nucleotide polymorphisms analysis, Sequence-Tagged-Site marker analyses, exome sequencing, and Sanger sequencing were performed.ResultsLinkage analyses identified a candidate locus on chromosome 9. Exome sequencing revealed a novel variant in LMX1B present in all affected individuals, logarithm of the odds (LOD) score of z = 6.54, predicted to be damaging. Nail-patella syndrome (NPS) is caused by pathogenic variants in LMX1B encoding a transcription factor essential to cytoskeletal and kidney growth and dopaminergic and serotonergic network development. NPS is characterized by abnormal musculoskeletal features and kidney dysfunction. Movement disorders have not previously been associated with NPS.ConclusionsParoxysmal dyskinesia is a heretofore unrecognized feature of the NPS spectrum. The pathogenic mechanism might relate to aberrant dopaminergic circuits. © 2020 International Parkinson and Movement Disorder Society.

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In vivo expression of putative LMX1B targets in nail-patella syndrome kidneys.

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| S-EPMC1377636 | biostudies-other

Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity.

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Novel LMX1B mutation in familial nail-patella syndrome with variable expression of open angle glaucoma.

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LMX1B haploinsufficiency due to variants in the 5'UTR as a cause of Nail-Patella syndrome.

Project description:Nail-Patella syndrome (NPS) is a rare autosomal dominant condition due to haploinsufficiency of LMX1B, caused by loss-of-function variants affecting the coding sequence, or partial/whole deletions of the gene. In here, we describe two familial cases of NPS, carrying novel variants of the LMX1B 5'UTR region (-174C>T and -226G>A). To verify their pathogenic role, we carried out a functional characterization, both by reporter gene assays in heterologous systems and in patient's derived cells. We demonstrated that both variants impair LMX1B expression at post-transcriptional level. They introduce two upstream open reading frames (uORFs), out-of-frame with the main LMX1B coding sequence, generating transcripts detected by the non-sense mediated decay (NMD). We also demonstrated that the escape of the altered mRNA from NMD, if any, may lead to the synthesis of an aberrant LMX1B protein.

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Novel missense mutation affecting the LIM-A domain of LMX1B in a family with Nail-Patella syndrome.

Project description:Nail-patella syndrome (NPS) is a rare autosomal dominant disease characterized by developmental defects of dorsal limb structures, the kidney, and the eye, that manifest as dysplastic nails, hypoplastic or absent patella, elbow dysplasia, iliac horns, glomerulopathy, and adult-onset glaucoma, respectively. This disorder is inherited in an autosomal dominant mode and is caused by heterozygous loss-of-function mutations in the LMX1B gene, which encodes the LIM homeodomain transcription factor LMX1B. In this study, we report the clinical findings of a Spanish family, from the Canary Islands, with three affected members who displayed varying phenotypes. DNA sequence analysis identified a novel heterozygous missense mutation in LMX1B, c.305A>G, p.(Y102C), that segregated with the disease. The tyrosine residue affected by the mutation is highly conserved in evolution, and is located in the LIM-A domain, next to one of the cysteine residues involved in zinc binding, suggesting that p.(Y102C) affects LMX1B function by disturbing its interactions with other proteins. Our results expand the mutation spectrum of LMX1B and provide insight into the molecular mechanisms of NPS pathology.

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Steroid-resistant nephrotic syndrome as the initial presentation of nail-patella syndrome: a case of a de novo LMX1B mutation.

Project description:BackgroundNail-patella syndrome (NPS) is an autosomal dominant disorder caused by mutations in the LMX1B gene and is characterized by nail dysplasia, skeletal abnormalities, and nephropathy. We herein report a case of steroid-resistant nephrotic syndrome (SRNS) prior to overt orthopedic symptoms in a patient with NPS.Case presentationA 24-year-old woman presented to our hospital with knee pain. She had poorly developed nails, hypoplastic patellas, dislocation of the elbows, and iliac horns in the pelvis. At the age of 7, she developed nephrotic syndrome and was diagnosed with primary focal segmental glomerulosclerosis by renal biopsy. She received long-term corticosteroid therapy with no obvious response. Her clinical course and orthopedic manifestations indicated NPS, and a genetic analysis showed a de novo mutation in the LMX1B gene (c.819 + 1G > A). Nephropathy in this case was considered to be associated with NPS. Therefore, we discontinued corticosteroids without the exacerbation of nephrotic syndrome.ConclusionsPatients with NPS may develop nephrotic syndrome prior to overt orthopedic symptoms and only show non-specific findings in renal biopsy at an early stage of NPS nephropathy. Hereditary nephrotic syndrome, often presenting as childhood-onset SRNS, may also be difficult to diagnose in patients with the following conditions: renal symptoms prior to overt extrarenal symptoms, de novo mutations, and non-specific findings in renal biopsy. Therefore, in the management of SRNS in children, we need to reconsider the possibility of hereditary diseases such as NPS even without a family history.

| S-EPMC5363042 | biostudies-literature

A microdeletion of chromosome 9q33.3 encompasses the entire LMX1B gene in a Chinese family with nail patella syndrome.

Project description:Nail patella syndrome (NPS) is an autosomal dominant disorder characterized by nail malformations, patellar apoplasia, or patellar hypoplasia. Mutations within the LMX1B gene are found in 85% of families with NPS; thus, this gene has been characterized as the causative gene of NPS. In this study, we identified a heterozygous microdeletion of the entire LMX1B gene using multiplex ligation-dependent probe amplification (MLPA) in a Chinese family with NPS. The determination of the deletion breakpoints by Illumina genome-wide DNA analysis beadchip showed that the deletion was located in chromosome 9q33.3 and spanned about 0.66 Mb in size. This heterozygous deletion provides strong evidence for haploinsufficiency as the pathogenic mechanism of NPS.

| S-EPMC4264161 | biostudies-literature

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