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CHROMOSOME ALIGNMENT-MAINTAINING PHOSPHOPROTEIN 1; CHAMP1

CHROMOSOME ALIGNMENT-MAINTAINING PHOSPHOPROTEIN 1; CHAMP1

Alternative titles; symbolsCAMP; CHAMPZINC FINGER PROTEIN 828; ZNF828CHROMOSOME 13 OPEN READING FRAME 8; C13ORF8KIAA1802HGNC Approved Gene Symbol: CHAMP1Cytogene...

Alternative titles; symbols

  • CAMP; CHAMP
  • ZINC FINGER PROTEIN 828; ZNF828
  • CHROMOSOME 13 OPEN READING FRAME 8; C13ORF8
  • KIAA1802

HGNC Approved Gene Symbol: CHAMP1

Cytogenetic location: 13q34 Genomic coordinates (GRCh38): 13:114,314,502-114,327,321 (from NCBI)

▼ Description
Proper attachment of microtubules to kinetochores is essential for accurate chromosome segregation. CHAMP1 is a zinc finger phosphoprotein required for maintenance of kinetochore-microtubule attachment and chromosome alignment on the metaphase plate (Itoh et al., 2011).

▼ Cloning and Expression
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2001) cloned CHAMP1, which they designated KIAA1802. The deduced protein contains 821 amino acids. RT-PCR ELISA detected moderate CHAMP1 expression in all adult and fetal tissues and specific adult brain regions examined.

By PCR of a human brain cDNA library, Itoh et al. (2011) cloned CHAMP1, which they called CAMP. The deduced 812-amino acid protein has 2 C2H2-type zinc finger motifs near its N terminus and 3 C2H2-type zinc finger motifs near its C terminus. The central region of CAMP contains 16 SPE motifs (consensus, PxxSPExxK), 10 WK motifs (SPxxWKxxP), and 6 FPE motifs (FPExxK). Immunofluorescence analysis of mitotic cells revealed CAMP localization along chromosome arms and on kinetochores and spindle fibers from prometaphase to anaphase. Database analysis detected CAMP orthologs in vertebrates, but not in worms, flies, or yeast.

▼ Gene Function
MAD2L2 (604094) has a central role in spindle assembly checkpoint, which assures proper kinetochore-microtubule attachment of all chromosomes prior to anaphase. By immunoprecipitation analysis of HEK293 cells expressing epitope-tagged MAD2L2, followed by mass spectrometric analysis, Itoh et al. (2011) found that CAMP bound MAD2L2. Depletion of CAMP in HeLa cells via small interfering RNA abolished spindle localization of MAD2L2 and reduced the number of chromosomes aligned on the metaphase plate. Knockdown of CAMP also caused rotation of the spindle axis, formation of multipolar spindles, and irregular K-fiber thickness. Live cell imaging of CAMP-knockdown cells showed delayed chromosome alignment, kinetochore-attached microtubules that never progressed into thick K-fibers, and kinetochore pairs that were gradually displaced from the metaphase plate during prolonged mitotic arrest. Mitotic phosphorylation of CAMP at multiple serines was essential for chromosome alignment. CAMP colocalized with CENPE (117143) and CENPF (600236) on kinetochores, but it did not interact directly with these proteins. Triple knockdown of CAMP, CENPE, and CENPF had no additive effect on chromosome alignment, suggesting that these proteins work in the same pathway. Domain analysis revealed that the WK region of CAMP bound MAD2L2, the SPE motifs were phosphorylated during mitosis, the FPE motifs were involved in spindle/kinetochore localization, and the C-terminal zinc finger domains of CAMP were involved in chromosome and spindle localization. The C-terminal domain of CAMP also had an inhibitory effect on chromosome alignment, and phosphorylation of serines in the FPE region relieved this inhibition.

▼ Mapping
Hartz (2015) mapped the CHAMP1 gene to chromosome 13q34 based on an alignment of the CHAMP1 sequence (GenBank AK074894) with the genomic sequence (GRCh38).

▼ Molecular Genetics
Using a combination of exome sequencing and array-based detection of chromosomal rearrangements, the Deciphering Developmental Disorders Study (2015) examined 1,133 children with severe undiagnosed developmental disorders and their parents. The authors identified 2 patients with autosomal dominant mental retardation-40 (MRD40; 616579), dysmorphic features, and congenital anomalies who had de novo loss-of-function mutations in the CHAMP1 gene (616327.0001-616327.0002). No functional studies were performed.

In 5 unrelated patients with MRD40, Hempel et al. (2015) identified 4 different de novo heterozygous truncating mutations in the CHAMP1 gene (616327.0003-616327.0006). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants were not performed, but all were predicted to result in a truncated protein lacking the functionally important C terminal domain which regulates CHAMP1 localization to chromosomes and the mitotic spindle, thereby providing a mechanistic understanding for their pathogenicity. One of the patients had been reported by Rauch et al. (2012).

▼ ALLELIC VARIANTS ( 6 Selected Examples):

.0001 MENTAL RETARDATION, AUTOSOMAL DOMINANT 40
CHAMP1, TRP334TER
In a boy with autosomal dominant mental retardation-40 (MRD40; 616579), the Deciphering Developmental Disorders Study (2015) identified a de novo heterozygous c.1002G-A transition in the CHAMP1 gene, resulting in a trp334-to-ter (W334X) substitution. Functional studies of the variant were not performed.

.0002 MENTAL RETARDATION, AUTOSOMAL DOMINANT 40
CHAMP1, ARG497TER
In a girl with autosomal dominant mental retardation-40 (MRD40; 616579), the Deciphering Developmental Disorders Study (2015) identified a de novo heterozygous c.1489C-T transition in the CHAMP1 gene, resulting in an arg497-to-ter (R497X) substitution. Functional studies of the variant were not performed.

.0003 MENTAL RETARDATION, AUTOSOMAL DOMINANT 40
CHAMP1, 2-BP DEL, 1866CA
In a 4-year-old boy (family A) of European descent with autosomal dominant mental retardation-40 (MRD40; 616579), Hempel et al. (2015) identified a de novo heterozygous 2-bp deletion (c.1866_1867delCA) in the CHAMP1 gene, resulting in a frameshift and premature termination (Asp622GlufsTer8). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 136), 1000 Genomes Project, or ExAC databases. Functional studies of the variant were not performed, but the mutation was predicted to result in a truncated protein lacking the functionally important C terminal domain.

.0004 MENTAL RETARDATION, AUTOSOMAL DOMINANT 40
CHAMP1, GLN590TER
In a 3-year-old boy (family B) of Dutch descent with autosomal dominant mental retardation-40 (MRD40; 616579), Hempel et al. (2015) identified a de novo heterozygous c.1768C-T transition in the CHAMP1 gene, resulting in a gln590-to-ter (Q590X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 136), 1000 Genomes Project, or ExAC databases. Functional studies of the variant were not performed, but the mutation was predicted to result in a truncated protein lacking the functionally important C terminal domain.

.0005 MENTAL RETARDATION, AUTOSOMAL DOMINANT 40
CHAMP1, ARG398TER
In an 18-year-old boy (family C) of Dutch descent with autosomal dominant mental retardation-40 (MRD40; 616579), Hempel et al. (2015) identified a de novo heterozygous c.1192C-T transition in the CHAMP1 gene, resulting in an arg398-to-ter (R398X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 136), 1000 Genomes Project, or ExAC databases. Functional studies of the variant were not performed, but the mutation was predicted to result in a truncated protein lacking the functionally important C terminal domain. Hempel et al. (2015) noted that the same de novo R398X mutation was identified by Rauch et al. (2012) in 1 of 51 individuals with severe intellectual disability who underwent trio exome-sequencing. This patient (family E) had a similar phenotype as patient C.

.0006 MENTAL RETARDATION, AUTOSOMAL DOMINANT 40
CHAMP1, 1-BP DEL, 635C
In a 3-year-old girl (family D) of Dutch descent with autosomal dominant mental retardation-40 (MRD40; 616579), Hempel et al. (2015) identified a de novo heterozygous 1-bp deletion (c.635delC) in the CHAMP1 gene, resulting in a frameshift and premature termination (Pro212LeufsTer7). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 136), 1000 Genomes Project, or ExAC databases. Functional studies of the variant were not performed, but the mutation was predicted to result in a truncated protein lacking the functionally important C terminal domain.

Tags: 13q34