Disturbed chromosome segregation and multipolar spindle formation in a patient with CHAMP 1 mutation

Abstract

BackgroundPatients with intellectual disability (ID) typically exhibit significant defects in both intelligence and adaptive behavior. Aberration of several genes involved in proper progression of mitosis has been reported to underlie ID. Here, we report a new patient with a novel mutation of CHAMP1.MethodsWhole exome sequencing (WES) analysis was performed. We isolated lymphoblast cells from the CHAMP1 patient and observed chromosome segregation.ResultsWe identified a de novo frameshift mutation in CHAMP1. We find that these cells exhibit an increase in centrosome number and resulting multipolar spindle formation. The phenotypes observed in the patient's lymphoblastoid cells were presumably because of cytokinesis failure. We also confirm the identical phenotypes in human culture cells depleted of CHAMP1.Conclusion CHAMP1 encodes a protein regulating kinetochore–microtubule attachment and chromosome segregation. These data strongly support that CHAMP1 mutations cause ID, and suggest that CHAMP1 is critical for progression of cytokinesis and maintenance of centrosome number.

CHAMP1 Mutations cause Refractory Infantile Myoclonic Epilepsy

“…One patient in Tanaka et al's 4 study had generalized seizures that started at the age of 3 years and were adequately treated with levetiracetam. Isidor et al 5 and Okamoto et al 6 have also reported one patient with epilepsy, each.…”

“…Okamoto et al 6 have recently reported a novel patient with a CHAMP1 mutation who had feeding difficulties, failure to thrive, delayed motor development, severely delayed acquisition of language skills, and intellectual disability. This patient showed spasticity of lower extremities, like the second patient we presented.…”

“…Since then, three series of patients with CHAMP1 mutations 2,4,5 and a clinical report of another patient, 6 which include 17 cases altogether were published. Hempel et al 2 firmly established mutations in CHAMP1 as the cause of a developmental disorder and provided the first detailed clinical description of CHAMP1-associated disorders.…”

First Chinese patient with mental retardation‑40 due to a de novo CHAMP1 frameshift mutation: Case report and literature review

“…Most patients have normal or nonspecific radiographs, while others exhibit slightly delayed myelination, cerebral atrophy and a decreased white matter volume (6,(12)(13)(14). For the patient of the present study, the bilateral lateral ventricular enlargement appeared to be nonspecific, and no abnormalities in the brain parenchyma were identified.…”

“…As a result, GDD/ID with speech delay, motor developmental delay and facial anomalies were observed in all patients, as well as hypotonia (17/18), abnormal muscular tone (16/18), vision damage (15/18), abnormal behaviors (14/18) and reproductive issues (13/18) were quite common in patients with MRD40, while seizures (4/18), abnormal hearing (3/18) and spasticity (4/18) were less prevalent phenotypes. The clinical features of the above-mentioned patients are listed in Table I (6,(12)(13)(14). In addition, all identified mutations in the CHAMP1 gene in patients diagnosed with MRD40 are truncating (nonsense or frameshift) mutations (Table II).…”