scholarly journals WNT11, a new gene associated with early-onset osteoporosis, is required for osteoblastogenesis

2021 ◽  
Author(s):  
Caroline Caetano Silva ◽  
Thomas Edouard ◽  
Melanie Fradin ◽  
Marion Aubert-Mucca ◽  
Manon Ricquebourg ◽  
...  
Keyword(s):  
Early Onset ◽  
Wnt Pathway ◽  
Loss Of Function ◽  
Mineral Density ◽  
Bone Cell Differentiation ◽  
Canonical Pathways ◽  
Lgr5 Expression ◽  
New Gene ◽  
U2os Cells ◽  
Mutant Cells

Abstract Monogenic early-onset osteoporosis (EOOP) is a rare disease defined by low bone mineral density (BMD) that results in increased risk of fracture in children and young adults. Although several causative genes have been identified, some of the EOOP causation remains unresolved. Whole-exome sequencing revealed a de novo heterozygous loss-of-function mutation in WNT11 (NM_004626.2:c.677_678dup p.Leu227Glyfs*22) in a 4-year-old boy with low BMD and fractures. We identified two heterozygous WNT11 missense variants (NM_004626.2:c.217G > A p.Ala73Thr) and (NM_004626.2:c.865G > A p.Val289Met) in a 51-year-old woman and in a 61-year-old woman respectively, both with bone fragility. U2OS cells with heterozygous WNT11 mutation (NM_004626.2:c.690_721delfs*40) generated by CRISPR-Cas9 showed reduced cell proliferation (30%) and osteoblast differentiation (80%) as compared with wild-type U2OS cells. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells, but recombinant WNT11 treatment rescued the expression of Wnt pathway target genes. Furthermore, the expression of RSPO2, a WNT11 target involved in bone cell differentiation, and its receptor LGR5, was decreased in WNT11 mutant cells. Treatment with WNT5A and WNT11 recombinant proteins reversed LGR5 expression, but WNT3A recombinant protein treatment had no effect on LGR5 expression in mutant cells. Moreover, treatment with recombinant RSPO2 but not WNT11 or WNT3A activated the canonical pathway in mutant cells. In conclusion, we have identified WNT11 as a new gene responsible for EOOP, with loss-of-function variant inhibiting bone formation via Wnt canonical and non-canonical pathways. WNT11 may activate Wnt signaling by inducing the RSPO2–LGR5 complex via the non-canonical Wnt pathway.

scholarly journals Early-Onset Osteoporosis

2021 ◽  
Author(s):  
Outi Mäkitie ◽  
M. Carola Zillikens
Keyword(s):  
Young Adults ◽  
Early Onset ◽  
Type I Collagen ◽  
Young Patients ◽  
Fragility Fractures ◽  
Underlying Disease ◽  
Bone Fragility ◽  
Sphingolipid Metabolism ◽  
Type I ◽  
Loss Of Function

AbstractOsteoporosis is a skeletal disorder with enhanced bone fragility, usually affecting the elderly. It is very rare in children and young adults and the definition is not only based on a low BMD (a Z-score < − 2.0 in growing children and a Z-score ≤ − 2.0 or a T-score ≤ − 2.5 in young adults) but also on the occurrence of fragility fractures and/or the existence of underlying chronic diseases or secondary factors such as use of glucocorticoids. In the absence of a known chronic disease, fragility fractures and low BMD should prompt extensive screening for secondary causes, which can be found in up to 90% of cases. When fragility fractures occur in childhood or young adulthood without an evident secondary cause, investigations should explore the possibility of an underlying monogenetic bone disease, where bone fragility is caused by a single variant in a gene that has a major role in the skeleton. Several monogenic forms relate to type I collagen, but other forms also exist. Loss-of-function variants in LRP5 and WNT1 may lead to early-onset osteoporosis. The X-chromosomal osteoporosis caused by PLS3 gene mutations affects especially males. Another recently discovered form relates to disturbed sphingolipid metabolism due to SGMS2 mutations, underscoring the complexity of molecular pathology in monogenic early-onset osteoporosis. Management of young patients consists of treatment of secondary factors, optimizing lifestyle factors including calcium and vitamin D and physical exercise. Treatment with bone-active medication should be discussed on a personalized basis, considering the severity of osteoporosis and underlying disease versus the absence of evidence on anti-fracture efficacy and potential harmful effects in pregnancy.

scholarly journals The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Maria A. Gandini ◽  
Ivana A. Souza ◽  
Laurent Ferron ◽  
A. Micheil Innes ◽  
Gerald W. Zamponi
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
Structural Damage ◽  
De Novo ◽  
Splice Variants ◽  
Cerebellar Atrophy ◽  
Familial Hemiplegic Migraine ◽  
Significant Loss ◽  
Loss Of Function ◽  
Hemiplegic Migraine

AbstractCACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming CaVα1 subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.

scholarly journals Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early-onset severe retinal dystrophy in microvillus inclusion disease subjects

2021 ◽  
Author(s):  
Andreas R. Janecke ◽  
Xiaoqin Liu ◽  
Rüdiger Adam ◽  
Sumanth Punuru ◽  
Arne Viestenz ◽  
...  
Keyword(s):  
Early Onset ◽  
Single Nucleotide Polymorphism Array ◽  
Outer Nuclear Layer ◽  
Retinal Dystrophy ◽  
Geographic Origin ◽  
Retinal Disease ◽  
Homozygosity Mapping ◽  
Rod Photoreceptor ◽  
Loss Of Function ◽  
Knockout Mouse Model

AbstractBiallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic—intestinal and retinal—disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.

scholarly journals Clinical, Genetics, and Bioinformatic Characterization of Mutations Affecting an Essential Region of PLS3 in Patients with BMND18

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Ting Chen ◽  
Haiying Wu ◽  
Chenxi Zhang ◽  
Jiarong Feng ◽  
Linqi Chen ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Homology Modelling ◽  
Gene Sequencing ◽  
Bioinformatic Analysis ◽  
Actin Binding ◽  
Clinical Genetics ◽  
Loss Of Function ◽  
Mineral Density ◽  
Trait Locus ◽  
The Impact

Background. Bone mineral density quantitative trait locus 18 (BMND18, OMIM #300910) is a type of early-onset osteogenesis imperfecta (OI) caused by loss-of-function mutations in the PLS3 gene, which encodes plastin-3, a key protein in the formation of actin bundles throughout the cytoskeleton. Here, we report a patient with PLS3 mutation caused BMND18 and evaluated all the reported disease-causing mutations by bioinformatic analysis. Methods. Targeted gene sequencing was performed to find the disease-causing mutation in our patient. Bioinformatic analyses mainly including homology modelling and molecular dynamics stimulation were conducted to explore the impact of the previously reported mutations on plastin-3. Results. Gene sequencing showed a novel nonsense mutation (c.745G > T, p.E249X), which locates at a highly conserved region containing residues p.240–266 (LOOP-1) in the PLS3 gene. Further bioinformatic analyses of the previously reported mutations revealed that LOOP-1 is predicted to physically connect the calponin-homology 1 (CH1) and CH2 domains of the ABD1 fragment and spatially locates within the interface of ABD1 and ABD2. It is crucial to the conformation transition and actin-binding function of plastin-3. Conclusions. This report identified a novel mutation that truncates the PLS3 gene. Moreover, bioinformatic analyses of the previous reported mutations in PLS3 gene lead us to find a critical LOOP-1 region of plastin-3 mutations at which may be detrimental to the integral conformation of plastin-3 and thus affect its binding to actin filament.

Loss of function TRPV6 variants are associated with chronic pancreatitis in nonalcoholic early-onset Polish and German patients

Pancreatology ◽  
2021 ◽  
Author(s):  
Grzegorz Oracz ◽  
Michał Zaród ◽  
Maren Ewers ◽  
Helmut Laumen ◽  
Tomasz Gambin ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Early Onset ◽  
Loss Of Function

scholarly journals Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

JAMA ◽  
2018 ◽  
Vol 320 (22) ◽  
pp. 2354 ◽  
Author(s):  
Seung Hoan Choi ◽  
Lu-Chen Weng ◽  
Carolina Roselli ◽  
Honghuang Lin ◽  
Christopher M. Haggerty ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Early Onset ◽  
Loss Of Function ◽  
Onset Atrial Fibrillation

scholarly journals Polyamine Homeostasis in Snyder-Robinson Syndrome

2018 ◽  
Vol 6 (4) ◽  
pp. 112 ◽  
Author(s):  
Tracy Murray-Stewart ◽  
Matthew Dunworth ◽  
Jackson Foley ◽  
Charles Schwartz ◽  
Robert Casero
Keyword(s):  
Tissue Transglutaminase ◽  
Decarboxylase Activity ◽  
Loss Of Function ◽  
Transport Activity ◽  
Spermine Synthase ◽  
Catabolic Enzymes ◽  
Polyamine Transport ◽  
Exogenous Spermine ◽  
Mutant Cells ◽  
Derivatives Of

Loss-of-function mutations of the spermine synthase gene (SMS) result in Snyder-Robinson Syndrome (SRS), a recessive X-linked syndrome characterized by intellectual disability, osteoporosis, hypotonia, speech abnormalities, kyphoscoliosis, and seizures. As SMS catalyzes the biosynthesis of the polyamine spermine from its precursor spermidine, SMS deficiency causes a lack of spermine with an accumulation of spermidine. As polyamines, spermine, and spermidine play essential cellular roles that require tight homeostatic control to ensure normal cell growth, differentiation, and survival. Using patient-derived lymphoblast cell lines, we sought to comprehensively investigate the effects of SMS deficiency on polyamine homeostatic mechanisms including polyamine biosynthetic and catabolic enzymes, derivatives of the natural polyamines, and polyamine transport activity. In addition to decreased spermine and increased spermidine in SRS cells, ornithine decarboxylase activity and its product putrescine were significantly decreased. Treatment of SRS cells with exogenous spermine revealed that polyamine transport was active, as the cells accumulated spermine, decreased their spermidine level, and established a spermidine-to-spermine ratio within the range of wildtype cells. SRS cells also demonstrated elevated levels of tissue transglutaminase, a change associated with certain neurodegenerative diseases. These studies form a basis for further investigations into the leading biochemical changes and properties of SMS-mutant cells that potentially represent therapeutic targets for the treatment of Snyder-Robinson Syndrome.

scholarly journals Early-Onset Parkinson Disease Screening in Patients From Nigeria

2021 ◽  
Vol 11 ◽  
Author(s):  
Lukasz M. Milanowski ◽  
Olajumoke Oshinaike ◽  
Benjamin J. Broadway ◽  
Jennifer A. Lindemann ◽  
Alexandra I. Soto-Beasley ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Parkinson Disease ◽  
Neurodegenerative Diseases ◽  
Early Onset ◽  
Local Population ◽  
Age At Onset ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
African Countries ◽  
Age Related

Introduction: Nigeria is one of the most populated countries in the world; however, there is a scarcity of studies in patients with age-related neurodegenerative diseases, such as Parkinson disease (PD). The aim of this study was to screen patients with PD including a small cohort of early-onset PD (EOPD) cases from Nigeria for PRKN, PINK1, DJ1, SNCA multiplication, and LRRK2 p.G2019S.Methods: We assembled a cohort of 109 Nigerian patients with PD from the four main Nigerian tribes: Yoruba, Igbo, Edo, and Hausa. Fifteen cases [14 from the Yoruba tribe (93.3%)] had EOPD (defined as age-at-onset &lt;50 years). All patients with EOPD were sequenced for the coding regions of PRKN, PINK1, and DJ1. Exon dosage analysis was performed with a multiplex ligation-dependent probe amplification assay, which also included a SNCA probe and LRRK2 p.G2019S. We screened for LRRK2 p.G2019S in the entire PD cohort using a genotyping assay. The PINK1 p.R501Q functional analysis was conducted.Results: In 15 patients with EOPD, 22 variants were observed [PRKN, 9 (40.9%); PINK1, 10 (45.5%); and DJ1, 3 (13.6%)]. Three (13.6%) rare, nonsynonymous variants were identified, but no homozygous or compound heterozygous carriers were found. No exonic rearrangements were present in the three genes, and no carriers of SNCA genomic multiplications or LRRK2 p.G2019S were identified. The PINK1 p.R501Q functional analysis revealed pathogenic loss of function.Conclusion: More studies on age-related neurodegenerative diseases are needed in sub-Saharan African countries, including Nigeria. Population-specific variation may provide insight into the genes involved in PD in the local population but may also contribute to larger studiesperformed in White and Asian populations.

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