LEMD3

Melorheostosis (MEL) is an uncommon, sclerosing disease, characterised by hyperostosis of long bones, resembling the flowing of candle wax. The disease is sporadic and the pathogenesis is still poorly understood. Occasionally, the same family can include individuals with MEL and Osteopoikilosis (OPK), a disease characterised by multiple round foci of increased bone density. LEMD3 gene mutations are related to OPK and Buschke-Ollendorff Syndrome, a genetic condition in which an association between MEL, OPK and skin lesions is observed...

Melorheostosis is an exceptionally rare sclerosing hyperostosis that typically affects the appendicular skeleton in a limited segmental fashion. It occasionally occurs on a background of another benign generalised sclerosing bone condition, known as osteopoikilosis caused by germline mutations in LEMD3, encoding the inner nuclear membrane protein MAN1, which modulates TGFβ/bone morphogenetic protein signalling. Recent studies of melorheostosis lesional tissue indicate that most cases arise from somatic MAP2K1 mutations although a small number may arise from other genes in related pathways, such as KRAS...

Osteopoikilosis (OPK) is a rare, benign, asymptomatic bone disease causing dense bone lesions, which could be interpreted as bone metastasis. The symmetric distribution, lack of bone destruction, and location differentiate OPK from metastatic disease. It is essential to be aware of this benign condition to prevent diagnostic errors. We present the case of a 10-year-old female patient with the concurrent diagnosis of secreting mixed germ cell tumor with Yolk Salk Tumor compound and OPK. Physical examination disclosed an abdominal mass, and blood tests showed increased alfa-fetoprotein and human chorionic gonadotropin levels...

Considerable diversity exists in porcine ear size, which is an important morphological feature of pig breeds. Previously, we localized four crucial candidate genes-high mobility group AT-hook 2 (HMGA2), LEM domain-containing 3 (LEMD3), methionine sulfoxide reductase B3 (MSRB3) and Wnt inhibitory factor 1 (WIF1)-on Sus Scrofa chromosome 5 affecting porcine ear size, then cloned LEMD3 and MSBR3. In this study, we performed rapid amplification of cDNA ends to obtain full-length cDNA sequences of 2338-bp WIF1 and 2998-bp HMGA2...

This corrects the article on p. 540 in vol. 37, PMID: 28840995.

BACKGROUND: Brain arteriovenous malformations (BAVM) represent a congenital anomaly of the cerebral vessels with a prevalence of 10-18/100 000. BAVM is the leading aetiology of intracranial haemorrhage in children. Our objective was to identify gene variants potentially contributing to disease and to better define the molecular aetiology underlying non-syndromic sporadic BAVM. METHODS: We performed whole-exome trio sequencing of 100 unrelated families with a clinically uniform BAVM phenotype...

Transforming growth factor-β (TGFβ) signaling through SMAD2/3 is an important driver of pathological fibrosis in multiple organ systems. TGFβ signaling and extracellular matrix (ECM) stiffness form an unvirtuous pathological circuit in which matrix stiffness drives activation of latent TGFβ, and TGFβ signaling then drives cellular stress and ECM synthesis. Moreover, ECM stiffness also appears to sensitize cells to exogenously activated TGFβ through unknown mechanisms. Here, using human fibroblasts, we explored the effect of ECM stiffness on a putative inner nuclear membrane protein, LEM domain-containing protein 3 (LEMD3), which is physically connected to the cell's actin cytoskeleton and inhibits TGFβ signaling...

A keloid is the process of skin healing, collagen synthesis and metabolism of the loss of normal control in a sustained hyperactive state, resulting in excessive proliferation of collagen fibers. A large-scale genome-wide association study (GWAS) has identified multiple single nucleotide polymorphisms (SNPs) in the 3q22.3 loci that are associated with keloids in a Japanese population. However, the associations of SNPs in 3q22.3 with keloids were not confirmed in a selected Chinese population by a replication study...

Osteopoikilosis is an inherited condition with autosomal dominant trait resulting in sclerotic foci throughout the skeleton. It has been suggested that loss-of-function mutations of LEMD3 gene located on 12q14.3 result in osetopoikilosis. A bp heterozygote deletion was detected in our patient at the cytosine nucleotide at position 1105 with molecular genetic analysis. Although this mutation has not been previously described, it was considered to be the most likely cause of the disease in our patient due to frame shift and premature stop codon formation...

Twelve families with exuberant and early-onset calcium pyrophosphate dehydrate chondrocalcinosis (CC) and diffuse idiopathic skeletal hyperostosis (DISH), hereafter designated DISH/CC, were identified in Terceira Island, the Azores, Portugal. Ninety-two (92) individuals from these families were selected for whole-genome-wide linkage analysis. An identity-by-descent (IBD) analysis was performed in 10 individuals from 5 of the investigated pedigrees. The chromosome area with the maximal logarithm of the odds score (1...

We report the case of a 6-year-old Caucasian girl with clinical and histopathologic features of Buschke-Ollendorff syndrome. Histologic examination of skin lesions showed thick, curly, elastic fibers in the derma. Bone lesions compatible with Buschke-Ollendorff syndrome were found in the girl's mother. Mutations in LEMD3 are pathogenic for Buschke-Ollendorff syndrome. Analysis of all exons and exon-intron junctions of LEMD3 did not reveal any germline mutations.

Osteopoikilosis is an autosomal dominant bone disorder characterized by symmetric multiple osteosclerotic lesions throughout the axial and appendicular skeleton. Pathogenic variants in the LEMD3 have been identified as the cause of osteopoikilosis. LEMD3 encodes an inner nuclear membrane protein that interacts with bone morphogenetic protein (BMP) and transforming growth factor (TGF)-β pathways. We report the case of a 19-year-old man presenting with lower back pain and sciatica. His radiograph revealed bilateral and symmetrical multiple osteosclerotic bone lesions in both scapular areas...

During spermiogenesis the spermatid nucleus is elongated, and dramatically reduced in size with protamines replacing histones to produce a highly compacted chromatin. After fertilisation, this process is reversed in the oocyte to form the male pronucleus. Emerging evidence, including the coordinated loss of the nuclear lamina (NL) and the histones, supports the involvement of the NL in spermatid nuclear remodelling, but how the NL links to the chromatin is not known. In somatic cells, interactions between the NL and the chromatin have been demonstrated: LEM-domain proteins and LBR interact with the NL and respectively, the chromatin proteins BAF and HP1...

PURPOSE OF REVIEW: Melorheostosis is a rare sclerosing bone dysplasia that affects both cortical bone and adjacent soft tissue structures in a sclerotomal distribution. In this review, we describe the natural history, radiological features, proposed pathogenesis, and management options for this debilitating condition. RECENT FINDINGS: Since its first description in 1922, about 400 cases of melorheostosis have been reported, either as single reports or in small case series...

Melorheostosis (MEL) is the rare sporadic dysostosis characterized by monostotic or polyostotic osteosclerosis and hyperostosis often distributed in a sclerotomal pattern. The prevailing hypothesis for MEL invokes postzygotic mosaicism. Sometimes scleroderma-like skin changes, considered a representation of the pathogenetic process of MEL, overlie the bony changes, and sometimes MEL becomes malignant. Osteopoikilosis (OPK) is the autosomal dominant skeletal dysplasia that features symmetrically distributed punctate osteosclerosis due to heterozygous loss-of-function mutation within LEMD3...

The 12q14 microdeletion syndrome is a rare condition characterized by low birth weight, failure to thrive, short stature, learning disabilities, and osteopoikilosis. To date, 20 cases of 12q14 deletion have been reported in the literature, displaying both phenotypic than genetic variability. We report on three familial cases, a mother and two brothers, with severe short stature. The mother and elder brother presented with osteopoikilosis while the younger brother had severe short stature and developmental delay...

Porcine ear size is an important characteristic for distinguishing among pig breeds. In a previous genome-wide association study of porcine ear size, LEM domain-containing 3 (LEMD3), methionine sulfoxide reductase B3 (MSRB3), high mobility group AT-hook 2 (HMGA2), and Wnt inhibitory factor 1 (WIF1) were implicated as important candidate genes for ear size. This study investigated the expression levels of four candidate genes for ear size in Erhualian and Large White pigs. Ten Erhualian pigs with large ears and eight Large White pigs with small ears at 60 days of age were examined...

To identify novel single nucleotide polymorphisms (SNPs) associated with venous thromboembolism (VTE) in African-Americans (AAs), we performed a genome-wide association study (GWAS) of VTE in AAs using the Electronic Medical Records and Genomics (eMERGE) Network, comprised of seven sites each with DNA biobanks (total ~39,200 unique DNA samples) with genome-wide SNP data (imputed to 1000 Genomes Project cosmopolitan reference panel) and linked to electronic health records (EHRs). Using a validated EHR-driven phenotype extraction algorithm, we identified VTE cases and controls and tested for an association between each SNP and VTE using unconditional logistic regression, adjusted for age, sex, stroke, site-platform combination and sickle cell risk genotype...

Introduction. Buschke-Ollendorf syndrome (BOS) is an uncommon syndrome characterized by osteopoikilosis and other bone abnormalities, accompanied by skin lesions, most frequently connective tissue nevi. BOS is caused by mutations in the LEMD3 gene, which encodes the inner nuclear membrane protein Man1. We describe a unique case of osteopoikilosis associated with late-onset localized scleroderma and familial LEMD3 mutations. Case Report. A 72-year-old woman presented with adult-onset diffuse morphea and bullous skin lesions...

BACKGROUND: We describe a male with functionally impairing radial deviation of the thumb who presented to us at 24 years of age. Two sclerotic skin lesions had been excised 7 years before because of consecutive skin contracture. Latest radiological examination showed a spotted pattern consistent with osteopoikilosis. CASE PRESENTATION: A corrective osteotomy of the thumb was carried out due to the patients discomfort. Facing the simultaneous osteo-cutaneous malformation we postulated a Buschke-Ollendorff syndrome...