Pleiotropic effect of a novel mutation in GCNT2 causing congenital cataract and a rare adult i blood group phenotype

Abstract

Mutations in GCNT2 have been associated with the rare adult i blood group phenotype with or without congenital cataract. We report a novel homozygous frameshift mutation c.1163_1166delATCA, p.(Asn388Argfs*20) as the cause of congenital cataract in two affected siblings. Blood group typing confirmed that both affected males have the rare adult i phenotype, supporting the hypothesis that the partial association of I/i phenotype and congenital cataract is due to the differential expression of GCNT2 isoforms.

Figure 1

Novel homozygous GCNT2 frameshift mutation in a CC family. (a) Pedigree of the study family with two affected siblings. Shaded squares denote affected males; dotted circles, carrier females; dotted square, carrier male. Arrowhead indicates proband in the family. (b) Exome sequence alignments of control (top panel) and individual II:3 (bottom panel) viewed using Integrative Genomics Viewer (https://www.broadinstitute.org/igv/) shows a 4-bp deletion in exon 3 of the GCNT2 gene in the proband (indicated by dashed box). Nucleotide sequences and corresponding amino acid residues are shown below the exome data tracks. (c) Sequence electropherograms demonstrate segregation of the GCNT2 mutation. The proband (II:3) and his affected brother (II:2) are homozygous for the 4-bp deletion. Their mother (I:2) and the children of II:2 (III:1 and III:2) are carriers for the mutation. Control sequence electropherogram is shown above I:2 sequence. The exon 3 mutation is predicted to cause a frameshift [c.1163_1166delATCA, p.(Asn388Argfs*20)]. GCNT2 cDNA is numbered in accordance with Ensembl transcript ID ENST00000316170, with +1 corresponding to the A of the ATG translation initiation codon.

Figure 2

GCNT2 gene structure and isoforms annotated with reported mutations. (a) All previously reported GCNT2 mutations, including homozygous and compound heterozygous missense mutations, a homozygous nonsense mutation and segmental deletions.^, Mutations in GCNT2 exon 2 or exon 3, or segmental deletions encompassing exons 1B, 1C, 2 and 3,^, were reported in patients with CC and an adult i blood group phenotype (Table 1), whereas the mutations in exon 1C (homozygous A169T/A169T and compound heterozygous A169T/R226Q) were found in patients with an adult i blood group phenotype without cataract (Table 1). The novel homozygous GCNT2 frameshift mutation identified in this study, p.(N388Rfs*20), is located in exon 3 (indicated by †). (b) Schematic of GCNT2 genomic structure with black bars representing coding exons (not to scale). Three alternatively transcribed exon 1 (1A, 1B and 1C) indicate exons used in different GCNT2 isoforms.^, (c) Three GCNT2 isoforms designated GCNT2-A, -B and -C result from alternative transcribed exon 1, but identical exon 2 and 3.^, The size of each protein isoform is also shown.