The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature

Meuwissen, Marije; Halley, Dicky; Smit, Liesbeth S.; Lequin, Maarten H.; Cobben, Jan Maarten; Coo, I.F.M. de; Harssel, Jeske van; Sallevelt, Suzanne C E H; Woldringh, G.H.; Knaap, Marjo S. van der; Vries, Linda S. de; Mancini, Grazia M.S.

doi:10.1038/gim.2014.210

Cited by 241 publications

(254 citation statements)

References 51 publications

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“…Soon after, heterozygous, semi-dominant pathogenic COL4A1 and COL4A2 mutations were identified in humans and in multiple mouse lines that model the pathology in patients 15–17 . Consistent with the broad distribution of α1(IV) 2 α2(IV) heterotrimers in nearly all basement membranes, COL4A1 and COL4A2 mutations cause multisystem disorders with abnormalities in the vasculature, brain, eyes, kidneys and muscles being the most commonly reported to date 18–20 . Cerebrovascular disease (CVD) is one of the most notable consequences of COL4A1 and COL4A2 mutations and comprises a growing constellation of clinical manifestations including porencephaly, small-vessel disease, leukoencephalopathy, intracranial aneurysms and recurrent intracerebral hemorrhages (ICH).…”

Section: ) Introductionmentioning

confidence: 78%

Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations

Jeanne¹,

Gould²

2017

Matrix Biology

115

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COL4A1 and COL4A2 are extracellular matrix proteins that form heterotrimers and are present in nearly all basement membranes in every organ. In the past decade, COL4A1 and COL4A2 mutations have been identified to cause a multi-system disorder for which penetrance and severity of constituent phenotypes can greatly vary. Here, we compare the outcomes of more than 100 mutations identified in patients and data from a murine allelic series to explore the presence of genotype-phenotype correlations – many of which are shared among other types of collagen. We find that there is a frequency bias for COL4A1 over COL4A2 mutations and that glycine (Gly) substitutions within the triple helical domain are the most common class of mutations. Glycine is most often replaced by a charged amino acid, however the position of the mutation, and not the properties of the substituting amino acid, appear to have a greater influence on disease severity. Moreover, the impact of position is not straightforward. Observations from a murine allelic series suggest that mutations in the NC1 domain may result in relatively mild phenotypes via a ‘quantitative’ mechanism similar to other types of collagens, however, this effect was not apparent in human reports. Importantly, other position-dependent effects had differential impacts depending on the phenotype of interest. For example, the severity of cerebrovascular disease correlated with an amino-to-carboxy severity gradient for triple-helical glycine substitutions whereas the penetrance and severity of myopathy and nephropathy appear to involve a functional sub-domain(s). Greater understanding of genotype-phenotype correlations and the interaction of consequences of different mutations will be important for patient prognosis and care and for developing mechanism-based therapeutics to treat individual components of this emerging syndrome.

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Section: ) Introductionmentioning

confidence: 78%

Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations

Jeanne¹,

Gould²

2017

Matrix Biology

115

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“…11 More recently, patients with COL4A1 mutations were reported with a variety of ASD phenotypes including microphthalmia, cataracts, Axenfeld-Rieger malformations and glaucoma. 6,[12][13][14][15][16][17][18][19][20][21][22][23] The disease spectrum in patients is broad and severity varies, as does the presence or absence of extraocular findings. For example, while most patients both have ocular and nonocular findings, one large family was reported with only isolated, nonsyndromic congenital cataracts in all 15 affected members.…”

Section: Resultsmentioning

confidence: 99%

“…5,6,15,17,20,23,32 In contrast, all 13 mutations in mice were identified primarily because of this phenotype. 5 Both observations could reflect ascertainment biases.…”

Section: Discussionmentioning

confidence: 99%

“…COL4A1 and COL4A2 are present in nearly every basement membrane and, accordingly, mutations in either gene cause multisystem disorders. 5,6 Although often cited for their involvement in cerebrovascular disease including porencephaly and hemorrhagic stroke, Col4a1 and Col4a2 point mutations were first identified in independent forward genetic screens in mice with cataracts and ocular dysgenesis. [7][8][9] Homozygous mutant mice are rarely viable 7,8,10 and complete COL4A1/COL4A2 deficiency is lethal.…”

Section: Resultsmentioning

confidence: 99%

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Strain-Dependent Anterior Segment Dysgenesis and Progression to Glaucoma inCol4a1Mutant Mice

Mao¹,

Smith

Alavi³

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Mao M, Smith RS, Alavi MV, et al. Strain-dependent anterior segment dysgenesis and progression to glaucoma in Col4a1 mutant mice. Invest Ophthalmol Vis Sci. 2015;56:6823-6831. DOI:10.1167/iovs.15-17527 PURPOSE. Mutations in the gene encoding collagen type IV alpha 1 (COL4A1) cause multisystem disorders including anterior segment dysgenesis (ASD) and optic nerve hypoplasia. The penetrance and severity of individual phenotypes depends on genetic context. Here, we tested the effects of a Col4a1 mutation in two different genetic backgrounds to compare how genetic context influences ocular dysgenesis, IOP, and progression to glaucoma.METHODS. Col4a1 mutant mice maintained on a C57BL/6J background were crossed to either 129S6/SvEvTac or CAST/EiJ and the F1 progeny were analyzed by slit-lamp biomicroscopy and optical coherence tomography. We also measured IOPs and compared tissue sections of eyes and optic nerves.RESULTS. We found that the CAST/EiJ inbred strain has a relatively uniform and profound suppression on the effects of Col4a1 mutation and that mutant CASTB6F1 mice were generally only very mildly affected. In contrast, mutant 129B6F1 mice had more variable and severe ASD and IOP dysregulation that were associated with glaucomatous signs including lost or damaged retinal ganglion cell axons and excavation of the optic nerve head.CONCLUSIONS. Ocular defects in Col4a1 mutant mice model ASD and glaucoma that are observed in a subset of patients with COL4A1 mutations. We demonstrate that different inbred strains of mice give graded severities of ASD and we detected elevated IOP and glaucomatous damage in 129B6F1, but not CASTB6F1 mice that carried a Col4a1 mutation. These data demonstrate that genetic context differences are one factor that may contribute to the variable penetrance and severity of ASD and glaucoma in patients with COL4A1 mutations.

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“…Al momento se han descrito casos de porencefalia familiar hereditaria con hemiplejía congénita atribuidos a mutaciones autosómica dominantes en el gen alfa-1 y 2 del colágeno tipo IV (COL4A1 y COL4A2) (3)(4)(5).…”

Section: Introductionunclassified

Epilepsia por porencefalia familiar: hallazgos clínicos, electroencefalográficos y de resonancia magnética.

Ramírez

F²

2017

Rev Neuropsiquiatr

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RESUMENLa porencefalia familiar es un trastorno genético raro que produce quistes porencefálico, los cuales son secundarios a un infarto vascular prenatal o perinatal. La hemiparesia congénita, el retardo mental y la epilepsia de grado variable son las manifestaciones más frecuentes. Se describe el caso de dos hermanos, uno varón y la otra mujer, quienes presentan hallazgos en imágenes de resonancia magnética cerebral de quistes porencefálicos extensos que comprometen las regiones fronto-parieto-temporales de un hemisferio distinto en cada uno. Ambos presentaban hemiparesia congénita, retardo mental y epilepsia medicamente tratable con hallazgos electro-clínicos, de imágenes y neuropsicológicos que permitieron localizar la zona epileptogénica sobre la región dorsolateral del lóbulo frontal yacente al quiste porencefálico. En pacientes con hemiparesia congénita, retardo mental y epilepsia con quiste porencefálico se debe considerar la posibilidad de porencefalia familiar e indagar antecedentes familiares de este trastorno.PALABRAS CLAVE: Quiste porencefálico, porencefalia familiar, epilepsia. SUMMARYFamilial porencephaly is a rare genetic disorder resulting in porencephalic cysts, which are secondary to prenatal or perinatal vascular infarction. Congenital hemiparesis, mental retardation, and epilepsy in variable degrees are the most frequent manifestations. We describe the case of two siblings, one male and the other female, who present findings in brain magnetic resonance imaging of extensive porencephalic cysts that compromise the fronto-parietaltemporal regions of a different hemisphere in each. Both presented congenital hemiparesis, mental retardation and medically treatable epilepsy with electro-clinical, imaging and neuropsychological findings allowed to locate the epileptogenic zone on the dorsolateral region of the frontal lobe lying to the porencephalic cyst. In patients with congenital hemiparesis, mental retardation and epilepsy with porencephalic cyst, the possibility of familial porencephaly should be considered and a family history of this disorder should be investigated.

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The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature

Cited by 241 publications

References 51 publications

Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations

Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations

Strain-Dependent Anterior Segment Dysgenesis and Progression to Glaucoma inCol4a1Mutant Mice

Epilepsia por porencefalia familiar: hallazgos clínicos, electroencefalográficos y de resonancia magnética.

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