Frame shift mutations of the ZMPSTE24 gene in two siblings with restrictive dermopathy

Matulevičienė, Aušra; Meškienė, Raimonda; Morkūnienė, Aušra; Ambrozaitytė, Laima; Meškauskas, Raimundas; Garunkštienė, Rasa; Drazdienė, Nijolė; Utkus, Algirdas; Kučinskas, Vaidutis

doi:10.1097/mcd.0000000000000100

Cited by 8 publications

(4 citation statements)

References 15 publications

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“…The exact pathogenetic mechanism of the fetal RD remains unclear, but it appears to involve a primary defect of collagen metabolism [22,23]. It is therefore suggested that RD was caused in most cases by ZMPSTE24 autosomal recessive mutations, or less frequently by LMNA autosomal-dominant mutations [24][25][26]. In the present study, we report the identification of two novel ZMPSTE24 gene Yunan Wang and Chang Liu contributed equally to this work.…”

Section: Introductionmentioning

confidence: 64%

Prenatal Diagnosis for Restrictive Dermopathy Caused by Novel Mutations in ZMPSTE24 Gene and Review of Clinical Features and Pathogenic Mutations Described in Literatures

Wang

Liu

Mai

et al. 2020

SN Compr. Clin. Med.

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Restrictive dermopathy (RD) is a rare disorder causing stillbirth or early neonatal death. Mutations in ZMPSTE24 and LMNA genes are reported as the causes of RD. In this report, we identified two novel, biparental-origin mutations of ZMPSTE24 gene in a family with two consecutive pregnancies demonstrated with prenatal ultrasonography features of RD. Considering the lethal outcome of RD, molecular genetic analysis has been applied in the prenatal diagnosis of their second affected fetus and the subsequent pregnancy. Moreover, we summarized the prenatal and postnatal features of RD patients, as well as pathogenic mutations described in the literature. Better awareness of clinical features and molecular pathogenesis of RD could be of significance in prenatal diagnosis and appropriate management of the disorder.

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Section: Introductionmentioning

confidence: 64%

Prenatal Diagnosis for Restrictive Dermopathy Caused by Novel Mutations in ZMPSTE24 Gene and Review of Clinical Features and Pathogenic Mutations Described in Literatures

Wang

Liu

Mai

et al. 2020

SN Compr. Clin. Med.

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“…The second translation initiation site corresponds to the M13-codon of the wild type protein (see illustration in Figure 2B). Analysis of published disease causing ZMPSTE24 mutations 10,11 and expression of ZMPSTE24(insT+M13I)-GFP (Figure 2F) revealed that all other potential in-frame start codons (=methionine codons) cannot act as physiological TISs to prevent complete loss of protein function.…”

Section: Methodsmentioning

confidence: 99%

Analysis of a non‐lethal biallelic frameshift mutation in ZMPSTE24 reveals utilization of alternative translation initiation codons

Kaufmann,

Pilic,

Auinger

et al. 2023

Clinical Genetics

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Restrictive dermopathy (RD) is a lethal condition caused by biallelic loss‐of‐function mutations in ZMPSTE24, whereas mutations preserving residual enzymatic activity of the ZMPSTE24 protein lead to the milder mandibuloacral dysplasia with type B lipodystrophy (MADB) phenotype. Remarkably, we identified a homozygous, presumably loss‐of‐function mutation in ZMPSTE24 [c.28_29insA, p.(Leu10Tyrfs*37)] in two consanguineous Pakistani families segregating MADB. To clarify how lethal consequences are prevented in affected individuals, functional analysis was performed. Expression experiments supported utilization of two alternative translation initiation sites, preventing complete loss of protein function consistent with the relatively mild phenotypic outcome in affected patients. One of these alternative start codons is newly formed at the insertion site. Our findings indicate that the creation of new potential start codons through N‐terminal mutations in other disease‐associated genes should generally be taken into consideration in the variant interpretation process.

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“…According to recent studies, the typical RD phenotype seems to be due to ZMPSTE24 null mutations and complete loss-of-function whereas less severe phenotypes could be associated with ZMPSTE24 haploinsufficiency or LMNA mutations (often called “RD-like phenotypes”) (Fig. 4c ) [ 97 , 98 ].…”

Section: Diseases Caused By Mutations Affecting Proteins Of the Outermentioning

confidence: 99%

Nuclear envelopathies: a complex LINC between nuclear envelope and pathology

Janin

Bauer

Ratti

et al. 2017

Orphanet J Rare Dis

102

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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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Frame shift mutations of the ZMPSTE24 gene in two siblings with restrictive dermopathy

Cited by 8 publications

References 15 publications

Prenatal Diagnosis for Restrictive Dermopathy Caused by Novel Mutations in ZMPSTE24 Gene and Review of Clinical Features and Pathogenic Mutations Described in Literatures

Prenatal Diagnosis for Restrictive Dermopathy Caused by Novel Mutations in ZMPSTE24 Gene and Review of Clinical Features and Pathogenic Mutations Described in Literatures

Analysis of a non‐lethal biallelic frameshift mutation in ZMPSTE24 reveals utilization of alternative translation initiation codons

Nuclear envelopathies: a complex LINC between nuclear envelope and pathology

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