Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth

Abstract

Existence of a discrete new X-linked intellectual disability (XLID) syndrome due to KIAA2022 deficiency was questioned by disruption of KIAA2022 by an X-chromosome pericentric inversion in a XLID family we reported in 2004. Three additional families with likely pathogenic KIAA2022 mutations were discovered within the frame of systematic parallel sequencing of familial cases of XLID or in the context of routine array-CGH evaluation of sporadic intellectual deficiency (ID) cases. The c.186delC and c.3597dupA KIAA2022 truncating mutations were identified by X-chromosome exome sequencing, while array CGH discovered a 70 kb microduplication encompassing KIAA2022 exon 1 in the third family. This duplication decreased KIAA2022 mRNA level in patients' lymphocytes by 60%. Detailed clinical examination of all patients, including the two initially reported, indicated moderate-to-severe ID with autistic features, strabismus in all patients, with no specific dysmorphic features other than a round face in infancy and no structural brain abnormalities on magnetic resonance imaging (MRI). Interestingly, the patient with decreased KIAA2022 expression had only mild ID with severe language delay and repetitive behaviors falling in the range of an autism spectrum disorder (ASD). Since little is known about KIAA2022 function, we conducted morphometric studies in cultured rat hippocampal neurons. We found that siRNA-mediated KIAA2022 knockdown resulted in marked impairment in neurite outgrowth including both the dendrites and the axons, suggesting a major role for KIAA2022 in neuron development and brain function.

KIAA2022 nonsense mutation in a symptomatic female

“…Height was typically two standard deviations below the mean and microcephaly was present in half. Mutations included an X-chromosome inversion with breakpoint in exon 1; a 70 kb microduplication containing exon 1; and two frameshift mutations (c.186delC and c.3597dupA) resulting in premature stop codons [Van Maldergem et al, 2013]. In the family with the X-chromosome inversion, one of the two obligate female carriers was evaluated and found to have a skewed X-inactivation pattern but remained asymptomatic [Cantagrel et al, 2004].…”

“…The phenotypic spectrum includes moderate to severe ID with autistic features, poor or absent speech, epilepsy, and mild facial dysmorphisms [Van Maldergem et al, 2013]. Thus far, all reported males with KIAA2022 mutations are symptomatic while all reported females are asymptomatic.…”

Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?

“…Recently, new genetic factors affecting neuritogenesis, growth cone changes, and vesicle and membrane trafficking have been identified as related to autism (Grice and Buxbaum 2006;Castermans et al 2010;Volders et al 2011;van Maldergem et al 2013). At least in a subgroup of patients, alterations in genes associated with neuronal vesicle trafficking (e.g., secretory carrier membrane protein 5-SCAMP5) coincide with the elaboration of mature synapses and may represent functional candidates for autism pathology (Castermans et al 2010).…”

“…Furthermore, length and branching of neurites were found to be dependent on the neural cell adhesion molecules called contactins (Mercati et al 2013). Impairment in neurite outgrowth, including both dendrites and axons, was associated with mutation in the gene for the purinergic receptor and was manifested by intellectual disability within an autism spectrum disorder (van Maldergem et al 2013). Another study associated gene encoding enzyme monoamine oxidase B and proteins involved in regulation of neurite outgrowth with autism pathology (Piton et al 2011).…”

Bioinformatic Analysis of Genes and MicroRNAs Associated With Atrioventricular Septal Defect in Down Syndrome Patients

“…KIAA2022 is also known as an X-linked mental retardation protein related to neurite extension (XPN), 31) and it plays a role in regulating cell-cell and cell-matrix adhesion and migration. 32) It has been shown that the dysregulated cell-cell and cell-matrix adhesion signaling pathways contribute to heart birth defects during heart organogenesis.…”