Peters Plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase

Abstract

Peters Plus syndrome is an autosomal recessive disorder characterized by anterior eye-chamber abnormalities, disproportionate short stature, and developmental delay. After detection of a microdeletion by array-based comparative genomic hybridization, we identified biallelic truncating mutations in the beta 1,3-galactosyltransferase-like gene (B3GALTL) in all 20 tested patients, showing that Peters Plus is a monogenic, primarily single-mutation syndrome. This finding is expected to put Peters Plus syndrome on the growing list of congenital malformation syndromes caused by glycosylation defects.

Figure 1.

Overview of the location of the mutations in the B3GALTL gene and the results of the RT-PCR of RNA isolated from fibroblasts. A, Genes present in the 1.5-Mb deletion found in two brothers with Peters Plus syndrome. B, 15 exons of the B3GALTL gene, with the localization of the mutations. C, B3GALTL protein, which consists of a transmembrane region (TMR), a stem region (SR), and a catalytic domain (CD). Both mutations (c.1020+1G→A and c.437+5G→A) are located in the stem region. D, Result of the nested RT-PCR of exons 7–11 of the BGALTL gene, with RNA derived from myoblasts (WT), RNA from fibroblasts of a father heterozygous for the c.1020+1G→A mutation (Het), and RNA from fibroblasts of his affected son with c.1020+1G→A_pat/del_mat (Hom). The patient shows a smaller band compared with the WT band, which indicates a skip of exon 8. Sequence analysis of this band is shown. The vertical line indicates the end of exon 7 and the beginning of exon 9. The RT-PCR of the father shows, in addition to the WT band, a skipped product with much less intensity. E, Result of the RT-PCR encompassing exons 4–7 of the BGALTL gene, with RNA derived from lymphocytes of a control individual (WT) and a patient with a c.1020+1G→A_mat/c.437+5G→A_pat genotype (Het). In addition to a faint WT band, the patient shows a smaller product that lacks exon 5. The sequence analysis of this smaller band confirms the skip of exon 5.

Figure 2.

Facial features of four patients with Peters Plus syndrome. Patients A and C are homozygous for the c.1020+1G→A mutation. Patient B has the c.1020+1G→A_mat/c.437+5G→A_pat genotype, and patient D has the c.1020+1G→A_pat/del_mat genotype. Note the Peters anomaly of the eyes, the long face, and the Cupid’s bow shape of the upper lip in all patients. Patients B and D have a repaired cleft lip and/or palate. Patient A is female; the rest are male.