Molecular characteristics
KIAA1109 is located at 4q27 and encodes kiaa1109, a protein of yet unknown function. KIAA1109 is highly expressed in the ovaries and moderately expressed in other adult and fetal tissues. In the central nervous system, the thalamus, subthalamic nucleus, cerebellum, amygdala and spinal cord were the regions with the highest expression of this gene. kiaa1109 protein is known to interact with other proteins which may hint at its function. It interacts with CTNNB1, a protein associated with a dominant form of intellectual disability (MIM #615075). It also interacts with three proteins implicated in cell division, PTPA, DNAJB1, and BUB3. Other lower-confidence kiaa1109 protein interactors include BAG2, which competes with HIP for binding to HSC70/HSP70 ATPase domain, DRC1, which encodes an important component of nexin-dynein complex that regulates the assembly of ciliary dynein, and SMAD2, which mediates TGF-β signalling. As such, kiaa1109 is potentially mainly involved in cell cycle control, particularly of the central nervous system.
Mutations and pathophysiology
Alazami et al. (2015) identified a homozygous variant c.1557T>A (NM_015312.3) in the KIAA1109 gene, resulting in a tyr519-to-ter substitution. Gueneau et al. (2018) identified 13 affected individuals from 10 unrelated families. The affected members of 6 families were homozygous for variants c.9149C>A (p.Pro3050His), for c.10153G>C (p.Gly3385Arg) (which affected two unrelated Tunisian families, suggesting a Tunisian founder effect of this variant), for c.1557T>A (p.Tyr519Ter), for c.11250—1G>A (r.11250_ 11465del, p.His3751_Arg3822del), and for c.12067G>T (p.Glu4023Ter). The other affected families displayed heterozygous variants for c.3986A>G (p.Tyr1329Cys) and c.5599G>A (p.Val1867Met), for c.2902C>T (p.Arg968Cys) and c.3611delA (p.Asn1204Thrfs*6), for c.4719G> A (p.Met1573Ile) and the de novo c.5873G>A (p.Arg1958Gln), and for c.997dupA (p.Ile333Asnfs*5) and the deletion g.123254885_123263438delinsG (c.11567_ 12352delinsG, p.Lys3856Argfs*44) (GenBank: NM_015312.3). All subjects compatible with life have mild missense variants, whereas many of the subjects incompatible with life carried homozygous or compound heterozygote truncating alleles.