Identification of Two Novel Mutations in COG5 Causing Congenital Disorder of Glycosylation

Abstract

Objective: This study reports a Chinese patient with a Congenital Disorder of Glycosylation (CDG) caused by compound-heterozygous mutations in the Conserved Oligomeric Golgi 5 (COG5) gene and thereby offers concrete evidence for early diagnosis.

Methods: The clinical manifestations, the results of laboratory examinations and genetic analysis of a 4-year-old Chinese girl with CDG are reported. We also reviewed previous CDG cases that involved COG5 mutations by comparing the phenotypes and genotypes in different cases.

Results: The patient was admitted to our hospital due to ataxia and psychomotor delay. The major clinical manifestations were postural instability, difficulty in walking, psychomotor delay, hypohidrosis, hyperkeratosis of the skin, and ulnar deviation of the right-hand fingers. Biochemical analyses revealed coagulation defect and liver lesions. Vision tests showed choroidopathy and macular hypoplasia. Whole-exome sequencing identified the hitherto unreported compound-heterozygous COG5 mutations, c.1290C > A (p.Y430X) and c.2077A > C (p.T693P). Mutation p.Y430X is nonsense, leading to a truncated protein. Mutation p.T693P is located at a highly conserved region, and thus the polar-to-non-polar substitution presumably affects the structure and function of COG5. According to the Human Genome Mutation Database Professional, there have been totally 13 CDG cases caused by 13 COG5 mutations. They are mainly characterized by psychomotor delay, hypotonia, ataxia, microcephaly, and hearing and visual abnormalities.

Conclusion: The clinical manifestations of the patient are mild but consistent with the clinical characteristics of the published COG5-CDG cases. The results of this study extend the spectrum of clinical and genetic findings in COG5-CDG.

Keywords: COG5 gene; ataxia; congenital disorder of glycosylation; genetic sequencing; psychomotor delay; visual abnormalities.

FIGURE 1

X-ray of the right hand and brain MRI of the patient. (A) Ulnar deviation of the right-hand ring finger and little finger (red lines). (B) Brain MRI results (red arrow shows the cerebella).

FIGURE 2

The results of the eye examination. (A) Multispectral retinal image analysis. Abnormal fluorescence on the left (a1) and right (a2) retinas. Mass shadows in the macular region of the choroid in the left (a3) and right (a4) eyes. (B) Optical coherence tomography (OCT) images. The fovea centralis was absent from the center of the macula lutea of the left (b1) and right (b2) retinas (red arrows). The retinal pigment layers were intact. (C) The results of the pattern visual evoked potential (PVEP). At 1-degree checks, the latencies of P100 were normal but the amplitudes of P100 were moderately reduced in the left eye (c1) and slightly in the right eye (c3). (c2,c4) At 0.25-degree checks, the latencies of P100 were significantly longer, and the amplitudes were severely reduced in both eyes.

FIGURE 3

The results of genetic sequencing. Two mutations were identified in COG5, (A) c.1290C > A (p.Y430X) and (B) c.2077A > C (p.T693P). (C,D) The father of the proband carried mutation c.1290C > A (p.Y430X), and her mother carried c.2077A > C (p.T693P). The compound-heterozygous mutations in the proband were inherited from her parents. (E) Thr693 is highly conserved across species and located in a highly conserved region. (F) Expression levels of COG5 (93 kDa), small band (around 45 kDa) and GAPDH (Reference, 35 kDa) were shown by western blotting. (G) Quantification of the protein levels. The expression level of COG5 proteins was lower in the patient compared with control. A unknown small band appeared in the patient’s sample but control.