Loss of tissue-type plasminogen activator causes multiple developmental anomalies

Abstract

Hydrocephalus and Dandy-Walker malformation are amongst the most common congenital brain anomalies. We identified three consanguineous families with both obstructive hydrocephalus and Dandy-Walker malformation. To understand the molecular basis of these anomalies, we conducted genome-wide sequencing in these families. We identified three homozygous truncating variants in the PLAT gene in the four affected family members. All of them showed tetraventricular hydrocephalus. In two individuals, a membrane at the inferior aspect of the fourth ventricle was likely the cause of their hydrocephalus. Three cases exhibited Dandy-Walker malformation, whereas the two oldest individuals displayed intellectual disability. PLAT encodes the tissue-type plasminogen activator, a serine protease whose main function is to cleave the proenzyme plasminogen to produce active plasmin. Interestingly, plasminogen deficiency has also been shown to cause obstructive hydrocephalus and Dandy-Walker malformation, suggesting that loss of PLAT causes these defects by disrupting plasmin production. In summary, we describe a recessive disorder characterized by obstructive hydrocephalus, Dandy-Walker malformation and intellectual disability in individuals with loss-of-function variants in PLAT. This discovery further strengthens the involvement of the plasminogen pathway in the pathogenesis of these developmental disorders.

Keywords: Dandy–Walker malformation; PLAT; hydrocephalus; intellectual disability; plasminogen.

Graphical Abstract

Figure 1

Brain images of four individuals with a loss of PLAT function. (A–C). MRI images from Individual 1.1 at 7 years of age. (A) Sagittal constructive interference in steady state (CISS) image. The arrow points to CSF flow artefacts (enlarged in the inset) suggesting the presence of a membrane (not visualized because of these artefacts) at the outlets of the fourth ventricle. (B) Axial T2 image showing significant enlargement of both lateral ventricles with frontal predominance and absent septum pellucidum and subependymal heterotopia (arrow). (C) Axial T2 image showing dilated 4th ventricle with turbulent cerebrospinal fluid. (D–F) Images from foetus 1.2 at 23 3/7 weeks of gestation. (D) Sagittal T2 image showing dilated fourth ventricle. (E). Axial T2 image showing dilatation of both lateral ventricles. (F). Oblique coronal image showing hypoplastic cerebellum (arrow) and dilated fourth ventricle. (G–I). MRI images from Individual 2.2 at 19 months of age. (G). Sagittal 3D Fiesta showing a membrane at the central outlet of the fourth ventricle (arrow). (H). Axial T2 reformat showing absent septum pellucidum, subependymal heterotopia and ventricular shunt with residual hydrocephalus. (I). Enlargement of fourth ventricle with dysplastic cerebellar hemispheres. (J–L). Axial CT-scan images from Individual 3.1 at 1 year of age, showing significant enlargement of both lateral ventricles (J, K) and the fourth ventricle (L).

Figure 2

Localization of truncating variants in PLAT. (A). Variants reported herein (R29*, W139* and c.1530+2T>G), and the previously reported variant (R35Ifs9*). Upper numbers represent the amino acid position, whereas lower numbers indicate the exons. Protein domains are represented using a colour code. Scheme created using Lollipop (https://proteinpaint.stjude.org/). (B–D) Pedigrees of the three families indicating the genotype at the PLAT locus in individuals who have undergone genetic testing. The black symbols represent the affected homozygous individuals. The half-filled symbols represent unaffected heterozygous individuals. The crossed-out triangle represents a termination of pregnancy.