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Pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) is a rare cerebral small vessel disease characterized by adult-onset dysarthria, pontine lacunes on MRI, progressive supratentorial white matter involvement, dementia and tetraparesis. Clinical onset typically occurs between the third and fifth decade. The causative gene, COL4A1, encodes the α1 chain of type IV collagen, a basement membrane component critical for vascular integrity. Pathogenic variants disrupting COL4A1 function lead to vessel fragility and ischemic infarcts predominantly in the pons. Diagnosis relies on concordant clinical, radiological and genetic findings. Early identification enables targeted surveillance and management of stroke risk.
A linkage and exome sequencing study in a large French PADMAL family identified a heterozygous c.*32G>T variant in a predicted miR-29 binding site within the 3′ untranslated region of COL4A1 that cosegregated with disease (cumulative LOD = 6.03) and was absent in controls ([PMID:27666438]). Sanger sequencing of 202 unrelated cerebral small vessel disease probands uncovered five additional heterozygous variants in the same miR-29 binding site, raising the total to six unrelated PADMAL cases ([PMID:27666438]). This evidence established a gain-of-function mechanism whereby disruption of miR-29-mediated suppression results in COL4A1 upregulation.
In the original PADMAL kindred, clinical and cranial MRI assessments demonstrated adult-onset dysarthria progressing to cognitive decline and tetraparesis. Pontine infarcts frequently preceded supratentorial white matter changes and clinical symptoms, highlighting the value of early MRI screening ([PMID:36786861]). No miR-29 binding site variants were detected in 874 sporadic stroke patients, underscoring the specificity of these COL4A1 alterations for PADMAL ([PMID:36786861]).
A 35-year-old male with recurrent pontine strokes and leukoencephalopathy was found to harbor a heterozygous exon 40 missense variant, c.343G>C (p.Thr1144Arg), which also segregated in his affected mother, confirming autosomal dominant inheritance and expanding the variant spectrum beyond 3′ UTR mutations ([PMID:37830085]).
A de novo PADMAL case in a patient with classic MRI and clinical features revealed the recurrent pathogenic c.*32G>T variant absent in both parents, demonstrating that COL4A1 miR-29 binding site variants can arise spontaneously and should be considered even without family history ([PMID:39976879]).
Functional luciferase reporter assays and RT-qPCR analyses in patient fibroblasts confirmed that miR-29 binding site disruption leads to increased COL4A1 transcript levels, consistent with a gain-of-function pathogenic mechanism. These in vitro data align with the observed vascular phenotype and pontine ischemic lesions ([PMID:27666438]).
Integration of genetic and functional data across eight probands, including familial and de novo cases with segregation in two kindreds and consistent upregulation in cellular assays, supports a Strong ClinGen gene–disease association. Further studies may refine variant-specific risks, but current evidence justifies inclusion of COL4A1 miR-29 binding site and coding region sequencing for early diagnosis of PADMAL. Key take-home: targeted COL4A1 analysis enables accurate diagnosis of PADMAL and informs clinical management.
Gene–Disease AssociationStrong8 probands (6 unrelated families and two case reports), segregation in two families (LOD=6.03), concordant functional upregulation data Genetic EvidenceStrong8 probands with heterozygous COL4A1 variants, including familial and de novo cases with autosomal dominant segregation Functional EvidenceModerateLuciferase reporter and RT-qPCR assays demonstrate COL4A1 upregulation by miR-29 binding site disruption ([PMID:27666438]) |