PMC:5777449 / 30875-37369 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/5777449","sourcedb":"PMC","sourceid":"5777449","source_url":"https://www.ncbi.nlm.nih.gov/pmc/5777449","text":"Discussion\nData aggregation of exome sequencing from multiple laboratories allowed associating homozygous and compound heterozygote variants in KIAA1109 with a syndrome that we suggest naming Alkuraya-Kučinskas syndrome (AKS), as these clinicians first described affected individuals at the severe and mild ends of the phenotype, respectively. AKS combines severe brain malformations (13 affected individuals out of 13), in particular hydrocephaly/ventriculomegaly (11/13) and corpus callosum agenesis (8/13) with arthrogryposis/contractures (10/13) and/or talipes valgus/talipes equinovarus/club foot (12/13) and heart defects (6/13).\nAKS presents multiple overlaps with Aase-Smith syndrome 1 (ASS1 [MIM: 147800]) characterized by arthrogryposis, hydrocephalus, Dandy-Walker malformation, talipes equinovarus, cardiac defects, and risks of stillbirth or premature death. However, the two described families with one father and two children affected30 and one mother and her affected daughter31 are suggestive of a dominant rather than a recessive mode of transmission. Consistent with the view that AKS and ASS1 have different etiologies, both ASS1-affected families presented individuals affected with cleft palate, a birth defect not present in the 13 KIAA1109 individuals described here, including those at the severe end of the phenotypic spectrum. Interestingly, we have identified by exome sequencing an individual with partially overlapping features carrying a single de novo variant in KIAA1109. Although we cannot exclude that a second variant is present outside of the open reading frame, we might, alternatively, be dealing (1) with a spurious association or (2) with another syndrome related to AKS and associated with single variants in KIAA1109, similar to the de novo and biallelic variation recently associated with mitochondrial dynamics pathologies.32 The high missense ExAC Z-score of KIAA1109 is compatible with such hypothesis. The identification of other similarly affected individuals will allow disentangling this conundrum.\nThe observed combination of intellectual disability, corpus callosum hypoplasia, hydrocephalus, and talipes equinovarus is also reminiscent of the constellation of features seen in the L1CAM-associated (neural cell adhesion molecule L1 [MIM: 308840]) HSAS (hydrocephalus due to congenital stenosis of aqueduct of sylvius [MIM: 307000]) and CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus [MIM: 303350]) syndromes. Whereas HSAS syndrome leads to neonatal or infant death, L1CAM variants survivors are described as affected by CRASH syndrome. Similarly, ten of the herein described AKS-affected case subjects did not survive past infancy (16 if accounting for undiagnosed miscarriages), whereas the living UK.II.1, LT.II.1, and LT.II.2 individuals presented other prominent features reported in CRASH syndrome, such as adducted thumbs, short stature, microcephaly, language impairment, and abnormalities of tone. L1CAM is a cell adhesion molecule that plays critical roles in neuronal migration and differentiation.33 Congenital joint contractures, limb deformities, hydrocephalus, corpus callosum agenesis, hypoplastic brainstem, cortical thinning, and high proportions of stillborn or neonatal death also are reminiscent of the PVHH (proliferative vasculopathy and hydranencephaly-hydrocephaly [MIM: 225790]) syndrome, a recessive disorder caused by variant in the transmembrane calcium transporter, FLVCR2 (feline leukemia virus subgroup C receptor 2 [MIM: 610865]).\nThe Drosophila ortholog of KIAA1109 named tweek is widely expressed but enriched in the brain lobes and in the ventral nerve cord.27 Neuronal phosphatidylinositol-4,5-bisphosphate [PI(4,5)P(2)] levels are critical in restricting synaptic growth via localization and activation of presynaptic Wiscott-Aldrich syndrome protein/WASP, a phenomenon dependent on tweek but not on bone morphogenetic protein signaling.34 The 5,005-amino-acid-long KIAA1109 protein is conserved from nematodes to vertebrates (Figure S8) in spite of a lack of recognizable domains, with the exception of a 22-residue amino-terminal transmembrane segment and a small central coiled-coil of 22 residues. It is described by specialists as an unconstrained peptide thought to adopt a definite conformation upon binding to its interactors.35 Consistent with this hypothesis, multiple high-throughput protein-protein interactions screens coupling near-endogenous expression levels with quantitative proteomics and mass spectrometry have identified human or mouse KIAA1109 interactors. For example, CTNNB1 (catenin beta-1), a protein associated with a dominant form of intellectual disability (MIM: 615075), interacts with two separate regions of KIAA1109.36 Another set of experiments showed high-confidence interactions with BUB3, DNAJB1, and PTPA, three proteins implicated in cell division.37 BUB3 participates to the spindle-assembly checkpoint signaling and the establishment of kinetochore-microtubule attachments. It inhibits the ubiquitin ligase activity of the anaphase-promoting complex (APC/C) by phosphorylating its activator CDC2. PTPA, one of four major Ser/Thr phosphatases, negatively controls cell growth and division. DNAJB1 (a.k.a. HSP40) interacts with HSP70 and stimulates its ATPase activity and its association with HIP. Interestingly, lower-confidence KIAA1109 protein interactors include BAG2 that competes with HIP for binding to the HSC70/HSP70 ATPase domain, as well as DRC1 and SMAD2. DRC1 (MIM: 615288) encodes a central component of the nexin-dynein complex that regulates the assembly of ciliary dynein and is associated with primary ciliary dyskinesia (MIM: 615294). SMAD2 (MIM: 601366) regulates cell proliferation, apoptosis, and differentiation through mediation of TGF-β signaling.\n\nConclusion\nWe propose that bi-allelic LoF and missense variants in KIAA1109 cause an autosomal-recessive brain malformation disorder with cerebral parenchymal underdevelopment ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, and cerebellar hypoplasia with brainstem dysgenesis, associated with club foot and arthrogryposis. Severe cases are incompatible with life. Although further studies have to be engaged, our findings suggest that KIAA1109 is potentially involved in cell cycle control, particularly of the central nervous system. 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