Deletion in COL4A2 is associated with a three-generation variable phenotype: from fetal to adult manifestations

Hausman-Kedem, Moran; Ben-Sira, Liat; Kidron, Debora; Ben‐Shachar, Shay; Straussberg, Rachel; Marom, Daphna; Ponger, Penina; Bar‐Shira, Anat; Malinger, G.; Fattal‐Valevski, Aviva

doi:10.1038/s41431-021-00880-3

Cited by 11 publications

(16 citation statements)

References 43 publications

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Section: Discussionmentioning

confidence: 99%

“…In our center, we routinely apply virtual gene panel (VP) testing based on exome sequencing (ES) data, and we achieved similar diagnostic yield in patients tested with VP and ES 14 ; previous multi-and single-center studies performed genetic testing by targeted gene panel sequencing or ES. 3,10,12 COL4A1 and COL4A2 encode for type IV collagens that are important basement membrane proteins, and they form heterotrimers whose assembly is initiated at the C-terminal noncollagenous domains. 15 Three potential pathogenic mechanisms have been hypothesized; (a) cytotoxic effect of mutant heterotrimers, (b) extracellular deficiency of normal heterotrimers and (c) dominantnegative effect of extracellular mutant proteins.…”

Section: F I G U R E 1 30 + 3-wk-old Female Fetus With Intracranial I...mentioning

confidence: 99%

“…However, to our knowledge, PMG represents a rather less common presentation of COL4A1 mutation‐related disease, often lining schizencephalic clefts 9–11 . It is of interest, however, that a pathogenic in‐frame deletion in COL4A2 was observed in a three‐generational family with some members affected with PMG, intraventricular hemorrhage and white matter changes 12 …”

Section: Introductionmentioning

confidence: 98%

“… 9 , 10 , 11 It is of interest, however, that a pathogenic in‐frame deletion in COL4A2 was observed in a three‐generational family with some members affected with PMG, intraventricular hemorrhage and white matter changes. 12 …”

Section: Introductionmentioning

confidence: 99%

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COL4A1 mutation‐related disorder presenting as fetal intracranial bleeding, hydrocephalus, and polymicrogyria

et al. 2022

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Fetal intracranial hemorrhage represents a rare event with an estimated prevalence of 1:10 000 pregnancies. We report a patient diagnosed prenatally with intracranial hemorrhage and ventriculomegaly carrying a novel, previously unreported, likely pathogenic variant in COL4A1. At the gestational age of 27 weeks, dilation of lateral ventricles was detected during a routine prenatal ultrasound scan, confirmed by prenatal MRI at 30 + 3 weeks of gestation.

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Section: Discussionmentioning

confidence: 99%

Section: F I G U R E 1 30 + 3-wk-old Female Fetus With Intracranial I...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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COL4A1 mutation‐related disorder presenting as fetal intracranial bleeding, hydrocephalus, and polymicrogyria

et al. 2022

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“…At present, COL4A2 mutation related phenotypes include prenatal and neonatal intracranial hemorrhage, cerebral perforating malformation, cerebral perforating malformation with cataract, focal cortical dysplasia, cerebral fissure malformation, childhood and youth stroke, sporadic delayed hemorrhagic stroke (Meuwissen et al, 2015;Ha et al, 2016). COL4A1 and COL4A2 mutations share common and variable phenotypes varying from mild to severe (Hausman-Kedem et al, 2021). COL4A2 mutations are mainly missense mutations with incomplete penetrance, in which epilepsy with brain perforating malformation is an important clinical feature (Chung et al, 2021;Itai et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

A new identified COL4A2 mutation contributes to astrocyte activation by activating JAK/STAT signaling in epilepsy

Wang

2022

Preprint

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COL4A2 is the encoding gene of the α2 chains of type IV collagen, and missense mutations of COL4A2 is correlated with multiple diseases. However, the association of COL4A2 mutations with epilepsy remains elusive. Here, we aimed to explore the function of COL4A2 mutations in the development of epilepsy. We performed a full spectrum of family-enhanced whole-exome sequencing on a family lineage and examined the genetic change on COL4A2 gene. The kainic acid (KA)-induced in vivo model and lipopolysaccharide (LPS)-induced in vitro model were established. The production and secretion of inflammation cytokines were measured by qPCR, western blotting, and ELISA assay. Neuron damages and astrocyte activation were checked by Nissle and GFAP immunofluorescence staining. One heterozygous variant was detected in the COL4A2 gene: c.1148C>T(p.Pro383Leu). COL4A2 mutation significant induced the exacerbation of seizures and impaired the learning and memory phenotype of the KA rats. COL4A2 mutation promoted the hippocampal astrocyte activation, enhanced hippocampal neuronal injury in the rats. The levels of iNOS, COX-2, IL-1β, IL-6, and TNF-α elevated in KA-treated rats and LPS-treated astrocytes were further induced by COL4A2 mutation. Mechanically, COL4A2 mutation stimulated JAK/STAT signaling. JAK2 and STAT3 phosphorylation was promoted by COL4A2 mutation and JAK/STAT signaling inhibitor WP1066 could blocked the effect in primary astrocytes and CTX-TNA cells. These data indicated that a new identified COL4A2 mutation contributed to astrocyte activation by activating JAK/STAT signaling in epilepsy. Our findings provided a novel mechanism and treatment target of COL4A2 related epilepsy.

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De novo RANBP2 variant in a fetal demise case with cerebral intraparenchymal hemorrhage

Meroni

Kalantari

Arossa

et al. 2023

American J of Med Genetics Pt A

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Fetal intracranial hemorrhage (ICH) may result from a wide array of causes, either associated with maternal or fetal risk factors. In the last decade, monogenic causes of susceptibility to fetal ICH have been described, in particular in association with COL4A1 and COL4A2 genes. A peculiar form of ICH is acute necrotizing encephalitis (ANE), which is characterized by a rapid‐onset severe encephalopathy following an abnormal inflammatory response to an otherwise banal infection. It usually affects healthy children and it is thought to be multifactorial, with a genetic predisposition. RANBP2 gene has been extensively associated with ANE susceptibility. We hereby present a unique case of a 42‐year‐old secundigravida with intrauterine fetal demise at 35 weeks of gestation. Trio‐based whole‐exome sequencing performed on both parents and fetal DNA showed a de novo likely pathogenic variant in the RANBP2 gene on 2q13. At the fetal autopsy, subtentorial hematoma and cerebral intraparenchymal hemorrhage were present. We speculate that this might be a new phenotypic presentation of RANBP2‐associated disease. However, more similar fetal cases need to be reported in order to reinforce this hypothesis.

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Deletion in COL4A2 is associated with a three-generation variable phenotype: from fetal to adult manifestations

Cited by 11 publications

References 43 publications

COL4A1 mutation‐related disorder presenting as fetal intracranial bleeding, hydrocephalus, and polymicrogyria

COL4A1 mutation‐related disorder presenting as fetal intracranial bleeding, hydrocephalus, and polymicrogyria

A new identified COL4A2 mutation contributes to astrocyte activation by activating JAK/STAT signaling in epilepsy

De novo RANBP2 variant in a fetal demise case with cerebral intraparenchymal hemorrhage

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