J Korean Med Sci.  2017 Nov;32(11):1885-1890. 10.3346/jkms.2017.32.11.1885.

A Mild Form of COG5 Defect Showing Early-Childhood-Onset Friedreich's-Ataxia-Like Phenotypes with Isolated Cerebellar Atrophy

Affiliations
  • 1Department of Pediatrics, Chonnam National University Medical School, Gwangju, Korea. ik052@jnu.ac.kr
  • 2Department of Microbiology, Chonnam National University Medical School, Gwangju, Korea.
  • 3Department of Neurology, Chonnam National University Medical School, Gwangju, Korea.
  • 4Department of Radiology, Chonnam National University Medical School, Gwangju, Korea.
  • 5School of Biological Sciences and Technology, Chonnam National University, Gwangju, Korea.

Abstract

Progressive cerebellar ataxias are rare diseases during childhood, especially under 6 years of age. In a single family, three affected siblings exhibited Friedreich's-ataxia-like phenotypes before 2 years of age. They had progressive cerebellar atrophy, intellectual disability, and scoliosis. Although their phenotypes were similar to those observed in patients with autosomal recessive cerebellar ataxias, other phenotypes (e.g., seizure, movement disorders, ophthalmologic disturbance, cardiomyopathy, and cutaneous disorders) were not noted in this family. Whole-exome sequencing of the family members revealed one potential heterozygous mutation (c.1209delG, NM_181733.2; p.Met403IlefsX3, NP_859422.2) of the gene encoding conserved oligomeric Golgi complex subunit 5 (COG5). The heterozygous deletion at the fifth base in exon 12 of COG5 caused a frameshift and premature stop. Western blotting of COG5 proteins in the skin tissues from an affected proband showed a significantly decreased level of full length COG5 and smaller, aberrant COG5 proteins. We reported a milder form of COG5 defect showing Friedreich's-ataxia-like phenotypes without hypotonia, microcephaly, and short stature that were observed in most patients with COG5 defect.

Keyword

Cerebellar Ataxia; Cerebellar Atrophy; COG5 Protein; Intellectual Disability; Scoliosis; Child

MeSH Terms

Atrophy*
Blotting, Western
Cardiomyopathies
Cerebellar Ataxia
Child
Exons
Golgi Apparatus
Humans
Intellectual Disability
Microcephaly
Movement Disorders
Muscle Hypotonia
Phenotype*
Rare Diseases
Scoliosis
Seizures
Siblings
Skin

Figure

  • Fig. 1 Family pedigree and brain MRI. (A) Family pedigree of the family with early-childhood-onset Friedreich's-ataxia-like phenotype and isolated cerebellar atrophy. (B) Midsagittal T1-weighted brain MRI in patients III-3 and III-4 (proband) showing cerebellar atrophy with enlarged interfolial spaces in the cerebellum. No abnormalities in other parts of brain parenchyma were noted. MRI = magnetic resonance imaging.

  • Fig. 2 Mutation analysis of the gene encoding COG5. (A) Bioinformatic prioritization for variants in WES. (B) Electropherograms showing the wild-type reference sequence of COG5 in the healthy mother, and a heterozygous deletion (arrow) at the fifth base in exon 12 of COG5 causing a frameshift and premature stop (c.1209delG, NM_181733.2; p.Met403IlefsX3, NP_859422.2) in the affected proband. (C) Western blotting of COG5 skin proteins from the affected proband and a healthy control with an anti-COG5 antibody. The proband had two bands at about 90 and 40 kDa, representing the normal and aberrant COG5 proteins, respectively. The level of full-length COG5 at about 90 kDa in the proband appears to be significantly decreased compared to that in the normal healthy control showing a single meaningful band. COG5 = conserved oligomeric Golgi complex subunit 5, WES = whole-exome sequencing, GQ = genotype quality score, GATK = Genome Analysis Toolkit, SNVs = single-nucleotide variants, MAF = minor allele frequency, ESP = Exome Sequencing Project, dbSNP = Single Nucleotide Polymorphism Database, KSNP DB = Korean Single Nucleotide Polymorphism Database, SIFT = Sorting Intolerant From Tolerant, Polyphen2 = Polymorphism Phenotyping v2, dbNSFP = Database for Nonsynonymous SNPs Functional Predictions, PhyloP = phylogenetic P value, MW = molecular weight.


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