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Eric Weh, Linda Reis, Rebecca Tyler, Elena Semina; Mutation analysis of B3GALTL in Peters Plus Syndrome and alike phenotypes. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3359.
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Peters Plus Syndrome (PPS) is a rare autosomal recessive disorder characterized by Peters’ Anomaly (or other anterior segment dysgenesis), brachydactyly, short stature and variable other features. A number of different causal variants in B3GALTL have been reported but genotype/phenotype correlations have not yet been established due to rarity of this condition and insufficient mutation data. To obtain additional information about B3GALTL mutations in PPS and related phenotypes, we evaluated 53 human patients for variation in this gene.
The sequence of B3GALTL was obtained for each patient using PCR primers specific to the coding exons and immediate surrounding intronic regions of B3GALTL. Sequence files were analyzed using Mutation Surveyor to identify potentially causative variations. TaqMan Copy Number probes were used to test for copy number mutations involving B3GALTL.
B3GALTL sequences were obtained from 53 probands affected by classic PPS or overlapping phenotypes; the screen was completed for all exons in 50 of the patients. We identified recessive B3GALTL mutations in all but one classic PPS case in our study: 3 patients were homozygous for c.660+1G>GA, and 4 patients were compound heterozygotes for the following alleles, c.660+1G>GA/c.1065-1 G>GA, c.459+1G>GA/c.660+1G>GA, 660+1G>GA/1234C>CT (p.R412RX), 660+1G>GA/c.165insA (pG56Rfs*10). A c.1045G>GA (p.D349DN) allele was identified in an additional patient that is still under study for other B3GALTL exons. Three of the identified alleles, c.165insA (pG56Rfs*10), c.1234C>CT (p.R412RX), c.1045G>GA (p.D349DN) are novel, predicted to be deleterious and are not reported in the EVS database. The remaining patients were negative for any causative mutations.
We identified three novel B3GALTL alleles associated with Peters’ Plus syndrome: two nonsense/frameshift and one missense mutation. The missense change p.D349DN alters the first amino acid in the catalytic core of B3GALTL which is predicted to be deleterious by PolyPhen-2 and SIFT and is the second missense mutation reported in B3GALTL. B3GALTL mutations appear to be strongly associated with classic cases of PPS involving all three features: anterior segment anomaly, short stature and brachydactyly with variable other defects. Other PPS-like conditions, despite a significant phenotypic overlap with classic PPS, are likely to be associated with mutations in other genetic factors.
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