Wolf–Hirschhorn syndrome and ectrodactyly: New findings and a review of the literature

Shanske, Alan; Yachelevich, Naomi; Ala‐Kokko, Leena; Leonard, Jay; Levy, Brynn

doi:10.1002/ajmg.a.33159

Cited by 8 publications

(2 citation statements)

References 24 publications

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“…Letm1 was identified in 1999 as one of the genes contributing to multi-system Wolf-Hirschhorn syndrome [57,58] a multi-system disorder involving loss of variable amounts of the short arm of chromosome 4 including Letm1. Letm1 encodes a mitochondrially targeted, membrane bound protein with 2 EF-hand motifs.…”

Section: Mitochondrial Calcium Dynamicsmentioning

confidence: 99%

Mitochondrial calcium and the regulation of metabolism in the heart

Williams¹,

Boyman²,

Lederer³

2015

Journal of Molecular and Cellular Cardiology

164

112

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Consumption of adenosine triphosphate (ATP) by the heart can change dramatically as the energetic demands increase from a period of rest to strenuous activity. Mitochondrial ATP production is central to this metabolic response since the heart relies largely on oxidative phosphorylation as its source of intracellular ATP. Significant evidence has been acquired indicating that Ca(2+) plays a critical role in regulating ATP production by the mitochondria. Here the evidence that the Ca(2+) concentration in the mitochondrial matrix ([Ca(2+)]m) plays a pivotal role in regulating ATP production by the mitochondria is critically reviewed and aspects of this process that are under current active investigation are highlighted. Importantly, current quantitative information on the bidirectional Ca(2+) movement across the inner mitochondrial membrane (IMM) is examined in two parts. First, we review how Ca(2+) influx into the mitochondrial matrix depends on the mitochondrial Ca(2+) channel (i.e., the mitochondrial calcium uniporter or MCU). This discussion includes how the MCU open probability (PO) depends on the cytosolic Ca(2+) concentration ([Ca(2+)]i) and on the mitochondrial membrane potential (ΔΨm). Second, we discuss how steady-state [Ca(2+)]m is determined by the dynamic balance between this MCU-based Ca(2+) influx and mitochondrial Na(+)/Ca(2+) exchanger (NCLX) based Ca(2+) efflux. These steady-state [Ca(2+)]m levels are suggested to regulate the metabolic energy supply due to Ca(2+)-dependent regulation of mitochondrial enzymes of the tricarboxylic acid cycle (TCA), the proteins of the electron transport chain (ETC), and the F1F0 ATP synthase itself. We conclude by discussing the roles played by [Ca(2+)]m in influencing mitochondrial responses under pathological conditions. This article is part of a Special Issue entitled "Mitochondria: From BasicMitochondrial Biology to Cardiovascular Disease."

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Section: Mitochondrial Calcium Dynamicsmentioning

confidence: 99%

Mitochondrial calcium and the regulation of metabolism in the heart

Williams¹,

Boyman²,

Lederer³

2015

Journal of Molecular and Cellular Cardiology

164

112

View full text Add to dashboard Cite

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“…Foot defects include congenital talipes equinovarus (Subrt, Blehova, & Sedlackova, 1969) and pes cavus (Coffin, 1968). Hand anomalies have been shown to display variable penetrance (Battaglia et al, 2015), ranging from the minor (clinodactyly, campodactyly, polydactyly) (Battaglia et al, 1999) to the medically significant (ectrodactyly) (Bamshad, O'Quinn, & Carey, 1998; Shanske, Yachelevich, Ala‐Kokko, Leonard, & Levy, 2010).…”

Section: Discussionmentioning

confidence: 99%

Hip displacement in Wolf–Hirschhorn syndrome: Report on three cases and review of associated musculoskeletal pathologies

Buddhdev

Sabir

Kokkinakis

et al. 2020

American J of Med Genetics Pt A

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Wolf-Hirschhorn syndrome is a rare genetic disease caused by a chromosomal deletion of the distal short arm of Chromosome 4. It is associated with multisystem abnormalities, including delayed growth, characteristic facial features, epilepsy, and skeletal abnormalities. We report three patients who developed hip displacement, and describe the occurrence of delayed and nonunion in patients who underwent corrective proximal femoral osteotomy for hip displacement. We also performed a literature review identifying common musculoskeletal presentations associated with the condition. Patients with Wolf-Hirschhorn Syndrome are at risk of hip displacement (subluxation), and we would advocate annual hip surveillance in this patient group.

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Molecular Mechanisms Underlying Pathogenic Missense Mutations

Eggert

Alexov

2014

Encyclopedia of Life Sciences

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Research has identified there is a multiplicity of plausible molecular effects caused by human genetic differences that may lead to human diseases. Although human deoxyribonucleic acid (DNA) variations and rare mutations may be manifested at different levels and different magnitudes, a single nucleotide polymorphism (SNP) to a missing chromosome or a single amino acid mutation to a truncated protein, the pathological effect is the malfunction of the cell or the corresponding organ. It is pointed out that pathological DNA defects can cause more than one phenotypic change to the wild‐type macromolecular characteristics, for example, alterations of macromolecular stability and a variation in the ability to interact with macromolecular partners. The main obstacles to predicting pathogenic DNA variations are the complexity of biological reactions and the difficulty of assessing the threshold of the change that will make it pathogenic. Although some small deviations from the wild‐type properties of a particular biomolecule or a network may be harmless and result in natural differences between individuals, the deviations of the same magnitude occurring in different molecule or network can be pathogenic. These diverse molecular mechanisms that induce the malfunctions are the primary focus of this review. Key Concepts: Molecular mechanisms of pathogenic mutations refer to the disease‐causing change of the wild‐type properties of the corresponding macromolecules and networks. It could be an effect altering a particular characteristic, for example, stability, but could also be a combination of several factors affecting normal function of the cell. The magnitude of change of the wild‐type characteristics alone cannot be used to predict whether a mutation is pathogenic. In some cases, a small deviation from the wild‐type properties can be deleterious, whereas in others, much larger changes are observed without a disease‐causing effect. Frequently, a detailed knowledge of the biological reactions that are involved is needed to discriminate the pathogenic mutations from harmless variations. Personalised medicine provides personalised or individualized medical care on the basis of an individual's DNA. The knowledge of an individual's DNA is emerging as a powerful tool for selecting the most efficient drug among several alternative drugs available in the market. A DNA defect in a particular gene may not be pathogenic if there is a compensatory mechanism accounting for dysfunctional product and if the dysfunctional product is not toxic for the cell.

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Wolf–Hirschhorn syndrome and ectrodactyly: New findings and a review of the literature

Cited by 8 publications

References 24 publications

Mitochondrial calcium and the regulation of metabolism in the heart

Mitochondrial calcium and the regulation of metabolism in the heart

Hip displacement in Wolf–Hirschhorn syndrome: Report on three cases and review of associated musculoskeletal pathologies

Molecular Mechanisms Underlying Pathogenic Missense Mutations

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