BASEMENT MEMBRANE DISORDERS - keywords
basement membrane disorders
references to basement membrane disorders
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Ballabh P (2014) Pathogenesis and Prevention of Intraventricular hemorrhage. Clin Perinatol March; 41(1): 47–67.
Breedveld G, de Coo IF, Lequin MH, Arts WF, Heutink P, Gould DB, John SW, Oostra B, Mancini GM. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. J Med Genet 2006;43(6):490-5.
Brown RH Jr, Grant PE, Pierson CR. Case records of the Massachusetts General Hospital. Case 35-2006. A newborn boy with hypotonia. N Engl J Med. 2006 Nov 16;355(20):2132-42.
Colin E, Sentilhes L, Sarfati A, Mine M, Guichet A, Ploton C, Boussion F, Delorme B, Tournier-Lasserve E, Bonneau D. Fetal intracerebral hemorrhage and cataract: think COL4A1. J Perinatol 2014;34(1):75-7.
Degerliyurt A, Ceylaner G, Kocak H, Bilginer Gürbüz B, Cihan BS, Rizzu P, Ceylaner S. A new family with autosomal dominant porencephaly with a novel Col4A1 mutation. Are arachnoid cysts related to Col4A1 mutations? Genet Couns 2012;23(2):185-93.
de Vries LS, Koopman C, Groenendaal F, Van Schooneveld M, Verheijen FW, Verbeek E, Witkamp TD, van der Worp HB, Mancini G. COL4A1 mutation in two preterm siblings with antenatal onset of parenchymal hemorrhage. Ann Neurol 2009;65(1):12-8.
Garel C, Rosenblatt J, Moutard ML, Heron D, Gelot A, Gonzales M, Miné E, Jouannic JM. Fetal intracerebral hemorrhage and COL4A1 mutation: promise and uncertainty. Ultrasound Obstet Gynecol 2013;41: 228-229.
Giorgio E, Vaula G, Bosco G, Giacone S, Mancini C, Calcia A, Cavalieri S, Di Gregorio E, Rigault De Longrais R, Leombruni S, Pinessi L, Cerrato P, Brusco A, Brussino A. Two families with novel missense mutations in COL4A1: When diagnosis can be missed. J Neurol Sci 2015;352(1-2):99-104.
Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS, Schimenti JC, Aguglia U, van der Knaap MS, Heutink P, John SW (2005) Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science 308:1167-1171.
Govaert P, Triulzi F, Dudink J (2020) The developing brain by trimester. Handb Clin Neurol 171:245-289.
Gunda B, Mine M, Kovács T, Hornyák C, Bereczki D, Várallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E. COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. J Neurol 2014;261(3):500-3.
Ha TT, Sadleir LG, Mandelstam SA, Paterson SJ, Scheffer IE, Gecz J, Corbett MA. A mutation in COL4A2 causes autosomal dominant porencephaly with cataracts. Am J Med Genet A 2016;170A(4):1059-63.
Kinoshita Y, Okudera T, Tsuru E, Yokota A. Volumetric analysis of the germinal matrix and lateral ventricles performed using MR images of postmortem fetuses. AJNR Am J Neuroradiol. 2001 Feb;22(2):382-8.
Kutuk MS, Balta B, Kodera H, Matsumoto N, Saitsu H, Doganay S, Canpolat M, Dolanbay M, Unal E, Dundar M. Is there relation between COL4A1/A2 mutations and antenatally detected fetal intraventricular hemorrhage? Childs Nerv Syst 2014;30(3):419-24.
Mancini GM, de Coo IF, Lequin MH, Arts WF (2004) Hereditary porencephaly: clinical and MRI findings in two Dutch families. Eur J Paediatr Neurol 8(1):45-54.
Meuwissen ME, Halley DJ, Smit LS, Lequin MH, Cobben JM, de Coo R, van Harssel J, Sallevelt S, Woldringh G, van der Knaap MS, de Vries LS, Mancini GM. The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. Genet Med 2015;17(11):843-53.
Mochida GH, Ganesh VS, Felie JM, Gleason D, Hill RS, Clapham KR, Rakiec D, Tan WH, Akawi N, Al-Saffar M, Partlow JN, Tinschert S, Barkovich AJ, Ali B, Al-Gazali L, Walsh CA. A homozygous mutation in the tight-junction protein JAM3 causes hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Am J Hum Genet 2010;87(6):882-9.
Niwa T, Aida N, Osaka H, Wada T, Saitsu H, Imai Y. Intracranial Hemorrhage and tortuosity of Veins Detected on Susceptibility-weighted Imaging of a Child with a Type IV Collagen α1 Mutation and Schizencephaly. Magn Reson Med Sci 2015;14(3):223-6.
Raets MM, Dudink J, Govaert P (2015) Neonatal disorders of germinal matrix. J Matern Fetal Neonatal Med 28 Suppl 1:2286-90.Takenouchi T, Ohyagi M, Torii C, Kosaki R, Takahashi T, Kosaki K. Porencephaly in a fetus and HANAC in her father: variable expression of COL4A1 mutation. Am J Med Genet A 2015;167A(1):156-8.
Vahedi K, Alamowitch S. Clinical spectrum of type IV collagen (COL4A1) mutations: a novel genetic multisystem disease. Curr Opin Neurol 2011;24(1):63-8.
Verbeek E, Meuwissen ME, Verheijen FW, Govaert PP, Licht DJ, Kuo DS, Poulton CJ, Schot R, Lequin MH, Dudink J, Halley DJ, de Coo RI, den Hollander JC, Oegema R, Gould DB, Mancini GM. COL4A2 mutation associated with familial porencephaly and small-vessel disease. Eur J Hum Genet 2012;20(8):844-51.
Vermeulen RJ, Peeters-Scholte C, Van Vugt JJ, Barkhof F, Rizzu P, van der Schoor SR, van der Knaap MS. Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. Neuropediatrics 2011;42(1):1-3.
Wareham, L.K., Baratta, R.O., Del Buono, B.J. et al. Collagen in the central nervous system: contributions to neurodegeneration and promise as a therapeutic target. Mol Neurodegeneration 19, 11 (2024).
Xu H, Hu F, Sado Y, Ninomiya Y, Borza DB, Ungvari Z, et al. Maturational changes in laminin, fibronectin, collagen IV, and perlecan in germinal matrix, cortex, and white matter and effect of betamethasone. J Neurosci Res. 2008 May 15;86(7):1482-500.
Xu L, Nirwane A, Yao Y. Basement membrane and blood-brain barrier. Stroke Vasc Neurol. 2018 Dec 5;4(2):78-82.
Yoneda Y, Haginoya K, Arai H, Yamaoka S, Tsurusaki Y, Doi H, Miyake N, Yokochi K, Osaka H, Kato M, Matsumoto N, Saitsu H. De novo and inherited mutations in COL4A2, encoding the type IV collagen α2 chain cause porencephaly. Am J Hum Genet 2012;90(1):86-90.
Yoneda Y, Haginoya K, Kato M, Osaka H, Yokochi K, Arai H, Kakita A, Yamamoto T, Otsuki Y, Shimizu S, Wada T, Koyama N, Mino Y, Kondo N, Takahashi S, Hirabayashi S, Takanashi J, Okumura A, Kumagai T, Hirai S, Nabetani M, Saitoh S, Hattori A, Yamasaki M, Kumakura A, Sugo Y, Nishiyama K, Miyatake S, Tsurusaki Y, Doi H, Miyake N, Matsumoto N, Saitsu H. Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. Ann Neurol 2013;73(1):48-57.
Zhao N, Pessell AF, Chung TD, Searson PC. Brain vascular basement membrane: Comparison of human and mouse brain at the transcriptomic and proteomic levels. Matrix Biol. 2025 Aug;139:1-13.
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collagen 4A mutations
The basement membrane (BM)/basal lamina is a vital component of the BBB (Xu et al. 2018, Zhao et al. 2025). The BM surrounds endothelial cells and pericytes to hold them in place. The 20–200 nm thick BM is a mixture of different classes of extracellular matrix proteins including structural proteins (collagen type IV); adhesion proteins (laminin, fibronectin); nidogen; heparan sulfate proteoglycans (perlecan, agrin) among others. Endothelial cells, astrocytes and pericytes all bind to the BM via specific receptors. Integrins are the major class of receptors expressed by all cell types in the neurovascular unit, and exist in different subclasses to allow binding to different components e.g., collagen or laminin. These proteins are synthesised by cells forming the BBB.
Integrins transduce signals by interacting with cytoplasmic protein kinases and activating Ca2+channels. The non-integrin receptor dystroglycan mediates binding to the proteoglycans and laminin. All cells of the neurovascular unit secrete components of the basement membrane. Matrix metalloproteinases (MMP) can actively digest the membrane, and are found up-regulated in inflammatory disease, e.g., multiple sclerosis. Several families of ligands and receptors constitute classes of axon guidance molecules. These ligand–receptor pairs can be either attractive or repulsive.
basement membrane disorders
matrix fragility-GMH
In the brain, two types of BM are found: an endothelial BM and a parenchymal BM, which are separated by pericytes. Under physiological conditions, the two BM layers are indistinguishable and look like one in areas without pericytes.
Transcriptomic data from human BM endothelial cells suggests that the main laminin isoform is laminin 321, while transcriptomic data from mice and proteomic data from mice and humans suggest that laminin 521 is the predominant isoform.
The supporting molecules agrin, perlecan, and nidogen are detected at significant levels, although only nidogen 1 is detected in the human transcriptomic data. Nidogen, also known as entactin, stabilises the collagen IV and laminin networks. There is a compensatory mechanism between nidogen-1 and nidogen-2, such that only deletion of both leads to severe BM defects and perinatal lethality. Perlecan seems dispensable for BM maintenance but is required during embryogenesis. No significant differences in human BM composition are observed in endothelium along the arterio-venous axis.
The description of perinatal intracranial haemorrhage in utero associated with collagen 4A mutations, and the fragility of sinusoids in preterm germinal matrix, have actualised research on the BM.
laminin mutations
collagen 4A2 antenatal
collagen 4A1 mild perinatal
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collagen 4A1 severe antenatal
collagen 4A mutations and haemorrhage
Autosomal dominant familial porencephaly related to COL4A1 pathogenic variants has been reported (Gould et al 2005, Breedveld et al 2006, Yoneda et al 2013, Meuwissen et al 2015, Alarcon et al. 2025): fluid-filled cavities in the brain, caused by antenatal or perinatal haemorrhage are detected by fetal or neonatal ultrasound, CT or MRI. In addition to porencephaly, imaging shows various degrees of periventricular leukoencephalopathy, lacunar infarction and calcification (Vahedi et al 2007, Meuwissen et al 2015).
after Wareham et al. 2024
Antenatal brain haemorrhage due to collagen 4A mutations is extensively documented with in utero detection, but it is often a neonatal sonographic finding. Currently, six collagen IV α-chains (COL4A1–6) are identified. Unlike COL4A3–6, which are more spatially and temporally restricted, COL4A1 and COL4A2 are present in almost all BMs and are highly conserved across species. Ablation of COL4A1/2 results in abnormal BM structure and embryonic lethality. In addition, mice with splice mutation lacking exon 41 of COL4A1 in both alleles die during embryogenesis, whereas those with such mutation in one allele show porencephaly and intracerebral haemorrhage. Loss of exon 41 of COL4A1 in both endothelial cells and pericytes contributes to cerebrovascular defects. Various missense mutations in COL4A1/2 lead to brain malformation and intracerebral haemorrhage. Two proα1(IV) chains, encoded by COL4A1, form trimers that contain, in addition, a proα2(IV) chain encoded by COL4A2; these are the major components of the basement membrane in many tissues. COL4A1 is abundant in vascular walls, providing stability and binding sites for extracellular matrix interactions. COL4A1 mutations render the vascular wall susceptible to disruption and may disturb extracellular matrix interactions with basement membranes, important for developmental processes.
The clinical spectrum of collagen COL4A1 mutations includes recurrent intracranial haemorrhage (ICH) in association with leukoencephalopathy in young adults, with or without a family history of infantile hemiparesis or ICH (Vahedi et al. 2007). Focal disruption of basement membranes is the proposed mechanism.
The spectrum of symptoms varies in degree of severity and age of onset, with wide intrafamilial heterogeneity. Typically, affected individuals present with infantile hemiparesis, seizures, intellectual disability, dystonia, stroke and/or migraine. First manifestations (including brain haemorrhage) occur in previously asymptomatic adults, and MRI brain anomalies can be clinically silent.
COL4A1 and COL4A2 mutations display a broad spectrum including porencephaly, variably associated with eye defects (congenital cataract is frequent, retinal arterial tortuosity, eye anterior segment anomaly of Axenfeld-Rieger type) and systemic findings (muscle cramps and/or serum CK elevation, kidney involvement, cerebral aneurysms, Raynaud phenomenon, cardiac arrhythmia, hemolytic anemia). There is broad phenotypic variation, reduced penetrance and a high de novo mutation rate.
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Mutations in merosin α2 (encoded by the laminin α2 gene) lead to merosin-deficient congenital muscular dystrophy (neonatal hypotonia) with polymicrogyria (Brown et al. 2006).
Laminin is a cruciform-shaped trimeric protein composed of five α, four β and three γ chains. Various combinations of these chains generate many isoforms. Although endothelial cells, pericytes and astrocytes all make laminin at the BBB, they synthesise different isoforms. Specifically, astrocyte-derived laminin-211 is predominantly found in parenchymal BM, whereas endothelial cell–derived laminin-411 and laminin-511 are mainly located in endothelial BM. Loss of astrocyte-derived laminin (laminin-211) leads to age-dependent BBB breakdown and intracerebral haemorrhage in knockout mice. Laminin α2 null mutants display postnatal BBB disruption.
These results suggest an indispensable role of astrocytic laminin in BBB maintenance. Unlike laminin α5 global knockout mice, laminin α4 null mutants are viable. They show compromised vascular integrity and haemorrhage at perinatal stage but not in adulthood. Since laminin α5 expression in the vasculature starts after birth, it is believed that loss of laminin α4 is compensated by laminin α5.
after Brown et al. 2006
occipital polymicrogyria in neonatal muscular dystrophy due to merosin deficiency
matrix fragility in preterms
Together with the basal lamina, fibronectin, present in the extracellular matrix, plays a role in providing structural stability of vessels. Xu et al. in 2008 found that fibronectin levels in the germinal matrix were significantly lower than in white matter or cerebral cortex. Fibronectin levels in white matter and cortex increased significantly with advancing GA, but not in GM (Ballabh 2014). Given that polymerization of fibronectin controls stability of the vasculature and that fibronectin null mice exhibit cerebral haemorrhage, deficient fibronectin in the germinal matrix is likely to contribute to the fragility of matrix vasculature. The expression of type IV collagen chains and perlecan are not different between cortex, WM or GM (Anström et al. 2005). Laminin α1 had a higher expression in GM compared with WM and cortex, the other chains do not differ. In beagle puppies, immunoreactivity of laminin and collagen V in the germinal matrix is greater at postnatal d4 compared to d1, and indomethacin treatment further increases the intensity of immune signals for laminin and collagen V (Ballabh 2014). This suggests that deficiencies of these two molecules in the germinal matrix of beagle puppies might contribute to local vascular weakness.
Kinoshita et al. 2001, Raets et al. 2015, Govaert et al. 2020:
- fragility of GM microvasculature is not likely due to lack of laminin or perlecan; collagen V may play a role
- fibronectin is significantly low in GM
- tight junction protein levels in GM are comparable with WM and cortex levels, but they are immature at 23 weeks PMA
- perivascular coverage by astrocyte end-feet is immature in GM
- prenatal use of glucocorticosteroids stabilizes GM vasculature.
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