Mandibuloacral Dysplasia Caused by<i>LMNA</i>Mutations and Uniparental Disomy

Bai, Shaochun; Lozada, Anthony; Jones, Marilyn C.; Dietz, Harry C.; Dempsey, Melissa A; Das, Soma

doi:10.1155/2014/508231

Cited by 12 publications

(10 citation statements)

References 17 publications

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“…It consists of globular head domain, linker regions, α-helical coiled coil domain and globular tail domain. Locations of the progeria LMNA mutations in this study were shown with molecular mechanism of mutant lamin A protein and clinical phenotype, as previously reported in [ 34 ] (p.Met540Thr) [ 29 ], (c.1824C>T) [ 30 ], (c.1968+1G>A) [ 31 ], (c.1968+2T>C), and [ 36 ] (c.2968G>A and c.1968+5G>A). Δ50 indicates the region of deletion in progerin, also present in ZMPSTE24 mutant progeria [ 32 ].…”

Section: Resultssupporting

confidence: 86%

“…Biallelic ZMPSTE24 mutations also cause accumulations of farnesylated lamin A and a varying degree of progeroid phenotypes, depending on the residual enzymatic activity of ZMPSTE24 [ 32 , 33 ]. In rare instances, a homozygous amino acid substitution of lamin A can present with a phenotype similar to HGPS or mandibuloacral dysplasia, as described in cases with [p.Met540Thr; p.Met540Thr] [ 34 ] and [p.Thr528Met; p.Met540Thr] [ 35 ].…”

Section: Resultsmentioning

confidence: 99%

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Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies

Horvath

Oshima

Martin

et al. 2018

Aging

533

572

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DNA methylation (DNAm)-based biomarkers of aging have been developed for many tissues and organs. However, these biomarkers have sub-optimal accuracy in fibroblasts and other cell types used in ex vivo studies. To address this challenge, we developed a novel and highly robust DNAm age estimator (based on 391 CpGs) for human fibroblasts, keratinocytes, buccal cells, endothelial cells, lymphoblastoid cells, skin, blood, and saliva samples. High age correlations can also be observed in sorted neurons, glia, brain, liver, and even bone samples. Gestational age correlates with DNAm age in cord blood. When used on fibroblasts from Hutchinson Gilford Progeria Syndrome patients, this age estimator (referred to as the skin & blood clock) uncovered an epigenetic age acceleration with a magnitude that is below the sensitivity levels of other DNAm-based biomarkers. Furthermore, this highly sensitive age estimator accurately tracked the dynamic aging of cells cultured ex vivo and revealed that their proliferation is accompanied by a steady increase in epigenetic age. The skin & blood clock predicts lifespan and it relates to many age-related conditions. Overall, this biomarker is expected to become useful for forensic applications (e.g. blood or buccal swabs) and for a quantitative ex vivo human cell aging assay.

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Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies

Horvath

Oshima

Martin

et al. 2018

Aging

533

572

View full text Add to dashboard Cite

show abstract

“…This attribute is distinct from intra‐sutural bones that are juxta‐sutural, and in sharp contrast with the normal appearance of the surrounding parietal bones. Wormian bones have been reported (but not illustrated) in patients with MADA [Shen et al, ; Bai et al, ] but failure of ossification of occipital bone was not mentioned. Wormian bones were also mentioned in three patients with MADB, but only illustrated once [Miyoshi et al, ].…”

Section: Discussionmentioning

confidence: 99%

Failure of ossification of the occipital bone in mandibuloacral dysplasia type B

Haye

Dridi

Lévy

et al. 2016

American J of Med Genetics Pt A

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Mandibuloacral dysplasia with type B lipodystrophy is a rare autosomal recessive disease characterized by atrophic skin, lipodystrophy, and skeletal features. It is caused by mutations in ZMPSTE24, a gene encoding a zinc metalloproteinase involved in the post-translational modification of lamin. Nine distinct pathogenic variants have been identified in 11 patients from nine unrelated families with this disorder. We report a 12-year-old boy with mandibuloacral dysplasia with type B lipodystrophy and a novel homozygous c.1196A>G; p.(Tyr399Cys) mutation in ZMPSTE24. The patient had typical dermatological and skeletal features of mandibuloacral dysplasia with type B lipodystrophy, sparse hair, short stature, mild microcephaly, facial dysmorphism, and a striking failure of ossification of the interparietal region of the occipital bone, up to the position where transverse occipital suture can be observed. Newly recognized signs for mandibuloacral dysplasia with type B lipodystrophy were gaze palsy and ptosis. Delayed closure of cranial sutures and Wormian bones have been described in three patients, but an ossification failure strictly limited to the occipital bone, as seen in the present patient, appears to be unique for mandibuloacral dysplasia with type B lipodystrophy. This observation illustrates that ZMPSTE24 could play a specific role in membranous ossification in the interparietal part of the squama (Inca bone) but not in the intracartilaginous ossification of the supraoccipital. This failure of ossification in the squama appears to be a useful feature for the radiological diagnosis of mandibuloacral dysplasia with type B lipodystrophy.

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“…Plasilova et al (2004) reported four MADB patients with a homozygous K542N (1626 G > C) mutation in the LMNA gene and this mutation is associated with more severe progeroid features. Another MADB patient with a compound heterozygous R471C/R527C mutation in the LMNA gene was reported by Cao and Hegele (2003) and a homozygous M540T mutation in the LMNA gene by Bai et al (2014).…”

Section: Resultsmentioning

confidence: 99%

Mandibuloacral dysplasia and LMNA A529V mutation in Turkish patients with severe skeletal changes and absent breast development

Özer¹,

Ünsal

Aktuna³

et al. 2016

Clinical Dysmorphology

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Mandibuloacral dysplasia (MAD) is an autosomal recessive disorder characterized by acroosteolysis (resorption of terminal phalanges), skin changes (hyperpigmentation), clavicular hypoplasia, craniofascial anomalies, a hook nose and prominent eyes, delayed closures of the cranial sutures, lipodystrophy, alopecia, and skeletal anomalies. MAD patients are classified according to lipodystrophy patterns: type A and type B. The vast majority of MAD cases are caused by LMNA gene mutations. MAD patients with type A lipodystrophy (MADA) have been reported to have LMNA R527H, A529V, or A529T mutations. In this report, we describe two MADA patients with progressive skeletal changes, absent breast development, and cataract in addition to the classical MAD phenotype. Both patients were found to be homozygous for the Ala529Val mutation of the LMNA gene. Our female patient is the oldest MADA patient (59 years old) who has ever been reported with the LMNA mutation and also the LMNA Ala529Val mutation. This study is the second report on MADA patients with a homozygous Ala529Val mutation.

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Mandibuloacral Dysplasia Caused byLMNAMutations and Uniparental Disomy

Cited by 12 publications

References 17 publications

Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies

Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies

Failure of ossification of the occipital bone in mandibuloacral dysplasia type B

Mandibuloacral dysplasia and LMNA A529V mutation in Turkish patients with severe skeletal changes and absent breast development

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