Pelger-Huët anomaly and Greenberg skeletal dysplasia: LBR-associated diseases of cholesterol metabolism

Turner, Elizabeth M.; Schlieker, Christian

doi:10.1080/21675511.2016.1241363

Cited by 16 publications

(18 citation statements)

References 40 publications

(24 reference statements)

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“…A very recent study based on CRISPR-Cas9 technology showed that LBR point mutations are associated with a reduced sterol C14 reductase activity due and a lower affinity of LBR for NAPDH (Fig. 4a ) [ 36 ].…”

Section: Inner Nuclear Membrane (Inm) Proteins and Inherited Diseasesmentioning

confidence: 99%

Nuclear envelopathies: a complex LINC between nuclear envelope and pathology

Janin

Bauer

Ratti

et al. 2017

Orphanet J Rare Dis

101

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Since the identification of the first disease causing mutation in the gene coding for emerin, a transmembrane protein of the inner nuclear membrane, hundreds of mutations and variants have been found in genes encoding for nuclear envelope components. These proteins can be part of the inner nuclear membrane (INM), such as emerin or SUN proteins, outer nuclear membrane (ONM), such as Nesprins, or the nuclear lamina, such as lamins A and C. However, they physically interact with each other to insure the nuclear envelope integrity and mediate the interactions of the nuclear envelope with both the genome, on the inner side, and the cytoskeleton, on the outer side. The core of this complex, called LINC (LInker of Nucleoskeleton to Cytoskeleton) is composed of KASH and SUN homology domain proteins. SUN proteins are INM proteins which interact with lamins by their N-terminal domain and with the KASH domain of nesprins located in the ONM by their C-terminal domain.Although most of these proteins are ubiquitously expressed, their mutations have been associated with a large number of clinically unrelated pathologies affecting specific tissues. Moreover, variants in SUN proteins have been found to modulate the severity of diseases induced by mutations in other LINC components or interactors. For these reasons, the diagnosis and the identification of the molecular explanation of “nuclear envelopathies” is currently challenging.The aim of this review is to summarize the human diseases caused by mutations in genes coding for INM proteins, nuclear lamina, and ONM proteins, and to discuss their potential physiopathological mechanisms that could explain the large spectrum of observed symptoms.

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Section: Inner Nuclear Membrane (Inm) Proteins and Inherited Diseasesmentioning

confidence: 99%

Nuclear envelopathies: a complex LINC between nuclear envelope and pathology

Janin

Bauer

Ratti

et al. 2017

Orphanet J Rare Dis

101

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“…Heterozygous LBR mutations lead to nuclear hyposegmentation of neutrophils without causing disease [ 6 , 59 , 87 ], while homozygous LBR mutations cause various malformations ranging from cardiac defects, brachydactyly and mental retardation (homozygous Pelger–Huët anomaly), severe skin disease (ichthyosis in mice) and prenatal death (Greenberg dysplasia) [ 6 , 87 ]. Mutations resulting in the Pelger–Huët anomaly are identified everywhere in the gene, while mutations causing Greenberg skeletal dysplasia are mainly found in the C -terminal region resulting in abnormality of the hydrophobic transmembrane domains [ 90 , 91 ]. Since mutations causing the Pelger–Huët anomaly result in bilobed neutrophil nuclei in heterozygotes and unsegmented, ovoid nuclei in homozygotes, the Pelger–Huët anomaly has been characterized mainly as a laminopathy [ 6 , 56 , 59 ].…”

Section: The Intricate Roles Of Lbr At the Nuclear Envelopementioning

confidence: 99%

“…Since mutations causing the Pelger–Huët anomaly result in bilobed neutrophil nuclei in heterozygotes and unsegmented, ovoid nuclei in homozygotes, the Pelger–Huët anomaly has been characterized mainly as a laminopathy [ 6 , 56 , 59 ]. On the contrary, as mutations associated with Greenberg skeletal dysplasia result in a deficiency of sterol reductase activity and in elevated levels of sterol intermediates, Greenberg dysplasia has been often characterized as a disease of cholesterol metabolism [ 12 , 87 , 89 , 91 ].…”

Section: The Intricate Roles Of Lbr At the Nuclear Envelopementioning

confidence: 99%

“…Truncated forms of LBR—depending on the half-life of the mutated protein and whether mutations are heterozygous or homozygous—lead to significantly reduced amounts of LBR at the INM, that may cause severe malformations ranging from hyposegmented nuclei in neutrophils and the Pelger–Huët anomaly to Greenberg dysplasia [ 87 , 91 ]. Similarly, mutations in the LBR gene that result in complete loss of its sterol reductase activity [ 12 ] are developmentally lethal in humans.…”

Section: The Intricate Roles Of Lbr At the Nuclear Envelopementioning

confidence: 99%

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Lamin B Receptor: Interplay between Structure, Function and Localization

Nikolakaki

Mylonis

Giannakouŕos

2017

Cells

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Lamin B receptor (LBR) is an integral protein of the inner nuclear membrane, containing a hydrophilic N-terminal end protruding into the nucleoplasm, eight hydrophobic segments that span the membrane and a short, nucleoplasmic C-terminal tail. Two seemingly unrelated functions have been attributed to LBR. Its N-terminal domain tethers heterochromatin to the nuclear periphery, thus contributing to the shape of interphase nuclear architecture, while its transmembrane domains exhibit sterol reductase activity. Mutations within the transmembrane segments result in defects in cholesterol synthesis and are associated with diseases such as the Pelger–Huët anomaly and Greenberg skeletal dysplasia, whereas no such harmful mutations related to the anchoring properties of LBR have been reported so far. Recent evidence suggests a dynamic regulation of LBR expression levels, structural organization, localization and function, in response to various signals. The molecular mechanisms underlying this dynamic behavior have not yet been fully unraveled. Here, we provide an overview of the current knowledge of the interplay between the structure, function and localization of LBR, and hint at the interconnection of the two distinct functions of LBR.

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“…3 It has been reported that the lamin B receptor (LBR) mutations are the cause of PHA in humans. 13 The lamin B receptor is an evolutionary conserved, multifunctional protein. 14 LBR is an inner nuclear membrane protein that anchors the lamina and the heterochromatin to the inner nuclear membrane and has been shown to be significant for the normal morphologic maturation of granulocytes.…”

Section: Introductionmentioning

confidence: 99%

Inherited Disorder: Pelger-Huët Anomaly

Hadžimusić¹

2017

HTIJ

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Unfamiliarity with the appearance of immature neutrophils and mature neutrophils with bilobed nuclei and coarse clumping of the nuclear chromatin can lead to their erroneous classification. Presence of Pelger-Huët cells might be mistaken for a shift to the left, which represents an increase in the number of un-segmented (band) neutrophils in the circulation. Pelger-Huët anomaly, rather rare disorder is an inherited failure of the nuclei of neutrophils (and also eosinophils) to mature to the normal segmented form. PHA occurs secondary to mutations in the lamin B receptor. Consequently, a left shift always appears to be present. However, distinguishing PHA with acquired or pseudo-Pelger-Huët anomaly (PPHA), which has very similar morphologic characteristics, but it is associated with different pathological states, is very important.

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Pelger-Huët anomaly and Greenberg skeletal dysplasia: LBR-associated diseases of cholesterol metabolism

Cited by 16 publications

References 40 publications

Nuclear envelopathies: a complex LINC between nuclear envelope and pathology

Nuclear envelopathies: a complex LINC between nuclear envelope and pathology

Lamin B Receptor: Interplay between Structure, Function and Localization

Inherited Disorder: Pelger-Huët Anomaly

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