COL4A1 – Familial Porencephaly

Type IV collagen α1 chain COL4A1 is a critical basement membrane component. Heterozygous pathogenic variants in COL4A1 are established as an autosomal dominant cause of familial porencephaly familial porencephaly, characterized by perinatal intracerebral hemorrhages and cystic brain lesions.

Initial case reports described fetal intracerebral hemorrhages on prenatal MRI in two infants with de novo COL4A1 mutations (PMID:21500141). Subsequent diagnostic screening of 183 index patients identified 21 distinct COL4A1 variants in children with porencephaly or parenchymal hemorrhage, with a 40% de novo mutation rate (PMID:25719457).

Inheritance is autosomal dominant with variable expressivity and reduced penetrance. Familial segregation of COL4A1 glycine substitutions was demonstrated in one multiplex porencephaly pedigree (PMID:23225343).

The variant spectrum is dominated by glycine substitutions within the triple-helix domain and splice-site disruptions. A representative mutation, c.2008G>A (p.Gly670Arg), exemplifies the recurrent glycine-replacement pattern destabilizing collagen stability (PMID:25719457).

Functional studies in patient cells and mouse models support dominant-negative and haploinsufficiency mechanisms. Splice-site and frameshift mutations undergo nonsense-mediated decay leading to reduced α1(IV) protein levels in fibroblasts (PMID:23065703), while Col4a1 missense mutant mice display intracerebral hemorrhages and activation of the unfolded protein response (PMID:20056676).

Collectively, genetic segregation and experimental data provide definitive evidence linking COL4A1 variants to familial porencephaly. Genetic testing for COL4A1 informs diagnosis, family counseling, and management. Key Take-home: Screening for COL4A1 mutations enables early diagnosis and risk stratification in familial porencephaly.

References

• Neuropediatrics • 2011 • Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI. PMID:21500141
• Genetics in medicine • 2015 • The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. PMID:25719457
• Annals of neurology • 2013 • Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly. PMID:23225343
• Human molecular genetics • 2013 • Novel COL4A1 mutations cause cerebral small vessel disease by haploinsufficiency. PMID:23065703
• Human molecular genetics • 2010 • Col4a1 mutation in mice causes defects in vascular function and low blood pressure associated with reduced red blood cell volume. PMID:20056676

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