A familial case of nail patella syndrome with a heterozygous in-frame indel mutation in the LIM domain of LMX1B

Mukai, Masayuki; Fujita, Haruyuki; Umegaki‐Arao, Noriko; Sasaki, Takashi; Yasuda-Sekiguchi, Fumiyo; Isojima, Tsuyoshi; Kitanaka, Susumu; Amagai, Masayuki; Kubo, Akiharu

doi:10.1016/j.jdermsci.2017.12.010

Cited by 6 publications

(5 citation statements)

References 10 publications

(31 reference statements)

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“…Intriguingly, sequencing of the shortened PCR products revealed the same splice variant with deletion of exon 2, leading to a frameshift and a downstream premature termination codon (p.Asp49Serfs*17). Our data confirm that NPS is caused by haploinsufficiency of LMX1B as previously reported (27).…”

Section: Discussionsupporting

confidence: 92%

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Electron Microscopic and Immunohistochemical Findings of the Epidermal Basement Membrane in Two Families with Nail-patella Syndrome

Shinkuma

Nakamura²,

Maehara³

et al. 2019

Acta Derm Venerol

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Nail-patella syndrome is caused by mutations in the LMX1B gene that lead to anomalies of dorsal-ventral limb patterning. Some patients show abnormalities of the glomerular basement membranes; however, little is known about the epidermal basement membrane. This study found no abnormalities in the epidermal basement membrane zone. This finding suggests that nail deformities can be caused by the abnormal development of dorsal limb structures rather than dysfunction of the epidermal basement membrane. Nail-patella syndrome is an autosomal dominant disorder characterized by nail dysplasia and skeletal anomaly. Some patients have been shown to have ultrastructural abnormalities of the glomerular basement membrane that result in nephrosis. However, little has been reported on the epidermal basement membrane in this condition. This paper reports 2 families with nail-patella syndrome. Direct sequencing analysis of LMX1B revealed that family 1 and family 2 were heterozygous for the mutations c.140-1G>C and c.326+1G>C, respectively. To evaluate the epidermal basement membrane zone, ultrastructural and immunohistochemical analyses were performed using skin specimens obtained from the dorsal thumb. Electron microscopy showed intact hemidesmosomes, lamina lucida, lamina densa, and anchoring fibrils. Immuno fluorescence studies with antibodies against components of the epidermal basement membrane zone revealed a normal expression pattern among the components, including type IV collagen. These data suggest that nail dysplasia in patients with nail-patella syndrome is not caused by structural abnormalities of the epidermal basement membrane.

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Section: Discussionsupporting

confidence: 92%

“…Genetic analysis of NPS has so far determined that haploinsufficiency of LMX1B leads to the clinical manifesta-tion of NPS (27). In this study, we evaluated 2 families with NPS.…”

Section: Discussionmentioning

confidence: 99%

Electron Microscopic and Immunohistochemical Findings of the Epidermal Basement Membrane in Two Families with Nail-patella Syndrome

Shinkuma

Nakamura²,

Maehara³

et al. 2019

Acta Derm Venerol

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“…Most LIMX1B mutations affect the LIM domains or the homeodomain by altering amino acids that are essential for the binding of zinc or amino acids essential for DNA binding, respectively. Functional studies of a few LMX1B mutations have shown reduced transcriptional activity and decreased DNA-binding ability, resulting in the partial or complete loss of LMX1B function (6,15,22). These and other results suggest that the main pathogenic USA) following the manufacturer's instructions.…”

Section: Mutation Analysismentioning

confidence: 83%

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

Claverie-Martı́n

Trindade

Garcia-Gonzalez

et al. 2019

IRDR

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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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“…NPS is caused by loss‐of‐function mutations in the LMX1B gene, which is expressed in several different tissues and implicated in the clinical phenotype (Dreyer et al., 1998; McIntoshI et al., 1998; Vollrath et al., 1998). The LMX1B gene variants may reduce transcriptional activity and lose the ability to bind DNA (Mukai et al., 2018; Sato et al., 2005). The open reading frame of LMX1B encodes 395 amino acids and contains two N‐terminal zinc‐binding LIM domains, one homeodomain, and a C‐terminal glutamine‐rich domain (Dreyer et al., 2000).…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel LMX1B nonsense variant associated with congenital talipes equinovarus by prenatal exome sequencing: A case report

Chen,

Xiang,

Xiao

et al. 2023

Molec Gen & Gen Med

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BackgroundCongenital talipes equinovarus (CTEV) is a rotational foot deformity that affects muscles, bones, connective tissue, and vascular or neurological tissues. The etiology of CTEV is complex and unclear, involving genetic and environmental factors. Nail‐patella syndrome is an autosomal dominant disorder caused by variants of the LIM homeobox transcription factor 1 beta gene (LMX1B, OMIM:602575). LMX1B plays a key role in the development of dorsal limb structures, the kidneys, and the eyes, and variants in this gene may manifest as hypoplastic or absent patella, dystrophic nails, and elbow and iliac horn dysplasia; glomerulopathy; and adult‐onset glaucoma, respectively. This study aimed to identify pathogenic variants in a fetus with isolated talipes equinovarus diagnosed by ultrasound in the second trimester, whose father exhibited dysplastic nails and congenital absence of bilateral patella.MethodsPrenatal whole‐exome sequencing (WES) of the fetus and parents was performed to identify the genetic variant responsible for the fetal ultrasound abnormality, followed by validation using Sanger sequencing.ResultsA novel heterozygous nonsense variant in exon 6 of LMX1B (c.844C>T, p.Gln282*) was identified in the fetus and the affected father but was not detected in any unaffected family members. This nonsense variant resulted in a premature termination codon at position 282, which may be responsible for the clinical phenotype through the loss of function of the gene product.ConclusionsOur study indicating that a fetus carrying a novel nonsense variant of LMX1B (c.844C>T, p.Gln282*) can exhibit isolated talipes equinovarus, which expands the LMX1B genotypic spectrum and is advantageous for genetic counseling.

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A familial case of nail patella syndrome with a heterozygous in-frame indel mutation in the LIM domain of LMX1B

Cited by 6 publications

References 10 publications

Electron Microscopic and Immunohistochemical Findings of the Epidermal Basement Membrane in Two Families with Nail-patella Syndrome

Electron Microscopic and Immunohistochemical Findings of the Epidermal Basement Membrane in Two Families with Nail-patella Syndrome

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

Identification of a novel LMX1B nonsense variant associated with congenital talipes equinovarus by prenatal exome sequencing: A case report

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