Novel LMNA mutations in Greek and Myanmar Patients with Progeroid Features and Cardiac Manifestations

Kandhaya‐Pillai, Renuka; Hisama, Fuki M.; Bucks, Stephanie A.; Yarzar, Soe; Korovou, Haroula; Martin, George M.; Oshima, Junko

doi:10.31491/apt.2020.06.021

Cited by 3 publications

(5 citation statements)

References 20 publications

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“…Previous reports of kidney manifestation showed proteinuria, including the nephrotic range ( 26 ). While the mutation of our case, c.898G > C ( p .Asp300His) in LMNA ( Figure 3 ), was previously reported in two cases ( 25 , 29 ), kidney involvement was not described. It is not a novel mutation, as the mutation was reported previously ( 25 , 29 ).…”

Section: Discussioncontrasting

confidence: 43%

“…While the mutation of our case, c.898G > C (p.Asp300His) in LMNA (Figure 3), was previously reported in two cases (25, 29), kidney involvement was not described. It is not a novel mutation, as the mutation was reported previously (25,29). However, it is an extremely rare mutation, so its frequency has not been reported in genomic databases, including GNOMAD or Clinvar.…”

Section: Discussionmentioning

confidence: 63%

“…The other case is a 23-year-old woman from Myanmar with progeroid features, including short stature, thin scalp hair, absent eyebrow and eyelashes, and a beaked nose. She suffered from hypertension, secondary amenorrhea, generalized lipodystrophy, bilateral carotid artery stenosis, and left ventricular hypertrophy ( 25 ). Another missense variant of the same nucleotide locus (c.898G > A, p .Asp300Asn) was found in a 31-year-old French man with progeroid features, osteoporosis, premature atheromatosis, lipoatrophy, and cerebral ischemic disease ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

“…Atypical progeroid syndrome (APS) is another type of progeria from LMNA mutation. APS is very rare, and until now, 69 patients with LMNA mutation have been reported worldwide (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). It is characterized by not having an accumulation of the Lamin A precursors (14,15) and is caused by heterozygous LMNA mutations other than c.1924C > T. The onset of APS symptoms is relatively late, and the life span of APS patients is generally longer than those of HGPS (12,14,15).…”

Section: Introductionmentioning

confidence: 99%

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Case report: Focal segmental glomerulosclerosis in a pediatric atypical progeroid syndrome

Jang

Ahn²,

Ko³

et al. 2022

Front. Pediatr.

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Atypical progeroid syndrome (APS) is a rare type of progeroid syndrome mainly caused by heterozygous missense mutations in the LMNA (MIM 150330) gene. APS has heterogeneous clinical manifestations, and its kidney manifestations, particularly in children, are rarely documented. Here, we report the first pediatric case of APS with focal segmental glomerulosclerosis (FSGS). A 10-year-old boy with progeroid features was referred to the nephrology clinic because of hyperuricemia. He had dark skin, protruding eyes, and beaked nose and was very thin, suggesting lipodystrophy. He had been treated for recurrent urinary tract infection during infancy, and liver biopsy for persisting hepatitis showed steatohepatitis. He also had hypertrophic cardiomyopathy (HCMP) with mitral and tricuspid valve regurgitation. Genetic studies were performed considering his multisystem symptoms, and he was diagnosed as having APS according to exome sequencing findings (c.898G > C, p.Asp300His of LMNA). During the first visit to the nephrology clinic, he had minimal proteinuria (urine protein/creatinine ratio of 0.23 mg/mg), which worsened during follow-up. In three years, his urine protein/creatinine ratio and N-acetyl-b-D-glucosaminidase/creatinine ratio increased to 1.52 and 18.7, respectively. The kidney biopsy result was consistent with findings of FSGS, peri-hilar type, showing segmental sclerosis of 1 (5%) glomerulus out of 21 glomeruli. An angiotensin receptor blocker was added to manage his proteinuria. This is the first pediatric report of FSGS in an APS patient with confirmed LMNA defect, who manifested progeroid features, lipodystrophy, HCMP with heart valve dysfunction, and steatohepatitis. Our case suggests that screening for proteinuric nephropathy is essential for managing APS patients since childhood.

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Section: Discussioncontrasting

confidence: 43%

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Case report: Focal segmental glomerulosclerosis in a pediatric atypical progeroid syndrome

Jang

Ahn²,

Ko³

et al. 2022

Front. Pediatr.

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“… 5 , 6 More than 20 such mutations have been described, mainly dominant missense ones such as p.Pro4Arg, p.Thr10lle, p.Ala57Pro, p.Leu59Arg, p.Glu111Lys, p.Arg133Leu, p.Asp136His, p.Glu138Lys, p.Leu140Arg, p.Ser143Phe, p.Glu145Lys, p.Glu159Lys, p.Asp300Asn, p.Asp300Gly, p.Asp300His, p.Asn466Lys, p.Glu578Val, p.Cys588Arg, and p.Arg644Cys. 5 , 25 Several of these mutations are far less severe than those causing HGPS and are found in individuals suspected to have WS on clinical grounds, but that lack mutations in the causative gene of classic WS (the WRN gene), denoted as atypical WS. 5 More details on atypical WS will be provided in the paragraphs of this review dedicated to WS.…”

Section: Progeroid Syndromes Resulting From Alterations Of the Nuclear Lamina Architecturementioning

confidence: 99%

Mutations Involved in Premature-Ageing Syndromes

Coppedè¹

2021

TACG

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Premature-ageing syndromes are a heterogeneous group of rare genetic disorders resembling features of accelerated ageing and resulting from mutations in genes coding for proteins required for nuclear lamina architecture, DNA repair and maintenance of genome stability, mitochondrial function and other cellular processes. Hutchinson–Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best-characterized progeroid syndromes referred to as childhood- and adulthood-progeria, respectively. This article provides an updated overview of the mutations leading to HGPS, WS, and to the spectrum of premature-ageing laminopathies ranging in severity from congenital restrictive dermopathy (RD) to adult-onset atypical WS, including RD-like laminopathies, typical and atypical HGPS, more and less severe forms of mandibuloacral dysplasia (MAD), Néstor-Guillermo progeria syndrome (NGPS), atypical WS, and atypical progeroid syndromes resembling features of HGPS and/or MAD but resulting from impaired DNA repair or mitochondrial functions, including mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome and mandibuloacral dysplasia associated to MTX2 (MADaM). The overlapping signs and symptoms among different premature-ageing syndromes, resulting from both a large genetic heterogeneity and shared pathological pathways underlying these conditions, require an expert clinical evaluation in specialized centers paralleled by next-generation sequencing of panels of genes involved in these disorders in order to establish as early as possible an accurate clinical and molecular diagnosis for a proper patient management.

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Nuclear Abnormalities in LMNA p.(Glu2Lys) Variant Segregating with LMNA-Associated Cardiocutaneous Progeria Syndrome

Wilke,

Wick,

Schwab

et al. 2024

Genes

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The LMNA gene encodes lamin A and lamin C, which play important roles in nuclear organization. Pathogenic variants in LMNA cause laminopathies, a group of disorders with diverse phenotypes. There are two main groups of disease-causing variants: missense variants affecting dimerization and intermolecular interactions, and heterozygous substitutions activating cryptic splice sites. These variants lead to different disorders, such as dilated cardiomyopathy and Hutchinson–Gilford progeria (HGP). Among these, the phenotypic terms for LMNA-associated cardiocutaneous progeria syndrome (LCPS), which does not alter lamin A processing and has an older age of onset, have been described. Here, we present the workup of an LMNA variant of uncertain significance, NM_170707.2 c. 4G>A, p.(Glu2Lys), in a 36-year-old female with severe calcific aortic stenosis, a calcified mitral valve, premature aging, and a family history of similar symptoms. Due to the uncertainty of in silico predictions for this variant, an assessment of nuclear morphology was performed using the immunocytochemistry of stable cell lines to indicate whether the p.(Glu2Lys) had a similar pathogenic mechanism as a previously described pathogenic variant associated with LCPS, p.Asp300Gly. Indirect immunofluorescence analysis of nuclei from stable cell lines showed abnormal morphology, including lobulation and occasional ringed nuclei. Relative to the controls, p.Glu2Lys and p.Asp300Gly nuclei had significantly (p < 0.001) smaller average nuclear areas than controls (mean = 0.10 units, SD = 0.06 for p.Glu2Lys; and mean = 0.09 units, SD = 0.05 for p.Asp300Gly versus mean = 0.12, SD = 0.05 for WT). After functional studies and segregation studies, this variant was upgraded to likely pathogenic. In summary, our findings suggest that p.Glu2Lys impacts nuclear morphology in a manner comparable to what was observed in p.Asp300Gly cells, indicating that the variant is the likely cause of the LCPS segregating within this family.

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Novel LMNA mutations in Greek and Myanmar Patients with Progeroid Features and Cardiac Manifestations

Cited by 3 publications

References 20 publications

Case report: Focal segmental glomerulosclerosis in a pediatric atypical progeroid syndrome

Case report: Focal segmental glomerulosclerosis in a pediatric atypical progeroid syndrome

Mutations Involved in Premature-Ageing Syndromes

Nuclear Abnormalities in LMNA p.(Glu2Lys) Variant Segregating with LMNA-Associated Cardiocutaneous Progeria Syndrome

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