B3GLCT – Peters Plus Syndrome

Peters Plus syndrome (PPS) is a rare autosomal recessive congenital disorder characterized by anterior segment dysgenesis (Peters anomaly), disproportionate short stature, developmental delay and variable systemic anomalies (PMID:16909395). B3GLCT encodes a β1,3-glucosyltransferase that extends O-fucose on thrombospondin type 1 repeats (TSRs) with glucose, a key step in a noncanonical ER quality-control pathway. Biallelic B3GLCT variants disrupt this glycosylation, leading to the multisystem phenotype of PPS.

Genetic evidence includes identification of biallelic truncating or splice-site mutations in 20 unrelated PPS patients (PMID:16909395) and four single‐case reports confirming novel homozygous variants (PMID:21067481; PMID:26684045; PMID:32253880; PMID:32204707). A cohort screen of 64 patients with classic or overlapping phenotypes yielded nine PPS‐positive cases, with the canonical c.660+1G>A splice‐donor variant accounting for the majority of alleles (PMID:23889335). No B3GLCT mutations were detected in patients lacking full PPS criteria, underscoring high specificity (PMID:23889335).

Segregation analysis in multiple families demonstrated co-segregation of homozygous or compound heterozygous B3GLCT variants in four multiplex kindreds (n=4 families) (PMID:18798333) and in five affected fetuses from two consanguineous pedigrees (PMID:23161355), totaling at least 19 additional affected relatives.

The variant spectrum comprises predominantly splice‐site mutations (c.660+1G>A, c.347+5G>A, c.597-2A>G) and loss-of-function alleles including c.1015C>T (p.Gln339Ter) and c.168dupA (p.Gly57ArgfsTer11) (PMID:23889335). The recurrent c.660+1G>A variant is a founder allele observed across diverse populations.

Functional studies confirm that PPS‐associated B3GLCT mutations abrogate enzyme activity and reduce protein stability in vitro (PMID:34058199). MS‐based glycan profiling demonstrated complete loss of Glcβ1-3Fuc moieties on patient-derived TSRs (PMID:18199743). Noncanonical ER quality-control assays revealed that POFUT2/B3GLCT‐mediated glycosylation marks folded TSRs for efficient secretion (PMID:25544610), and B3glct-null mice recapitulate key PPS features including hydrocephalus and ocular anomalies (PMID:31600785; PMID:27687499).

No credible conflicting evidence has emerged. The robust genetic and mechanistic data establish a definitive association between B3GLCT and PPS. Key take-home: molecular testing of B3GLCT provides definitive diagnosis and guides genetic counseling in Peters Plus syndrome.

References

• American journal of human genetics • 2006 • Peters Plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase. PMID:16909395
• Ophthalmic genetics • 2010 • A novel nonsense B3GALTL mutation confirms Peters plus syndrome in a patient with multiple malformations and Peters anomaly. PMID:21067481
• Cornea • 2016 • Unique Presentation of Corneal Opacity in Peters Plus Syndrome: An Unusual Form of Peters Anomaly Showing Tissue Repair in Serial Analysis. PMID:26684045
• The Turkish journal of pediatrics • 2020 • Peters Plus syndrome: a recognizable clinical entity. PMID:32253880
• BMC ophthalmology • 2020 • Peters plus syndrome and Chorioretinal findings associated with B3GLCT gene mutation - a case report. PMID:32204707
• Clinical genetics • 2014 • Novel B3GALTL mutations in classic Peters plus syndrome and lack of mutations in a large cohort of patients with similar phenotypes. PMID:23889335
• American journal of medical genetics. Part A • 2008 • Mutation analysis of B3GALTL in Peters Plus syndrome. PMID:18798333
• Prenatal diagnosis • 2013 • Hydrocephalus, agenesis of the corpus callosum, and cleft lip/palate represent frequent associations in fetuses with Peters' plus syndrome and B3GALTL mutations. PMID:23161355
• The Journal of biological chemistry • 2008 • Peters Plus syndrome is a new congenital disorder of glycosylation and involves defective Omicron-glycosylation of thrombospondin type 1 repeats. PMID:18199743
• Current biology : CB • 2015 • Peters plus syndrome mutations disrupt a noncanonical ER quality-control mechanism. PMID:25544610
• Scientific reports • 2016 • Impaired ADAMTS9 secretion: A potential mechanism for eye defects in Peters Plus Syndrome. PMID:27687499
• Human molecular genetics • 2019 • ADAMTS9 and ADAMTS20 are differentially affected by loss of B3GLCT in mouse model of Peters plus syndrome. PMID:31600785
• The Journal of biological chemistry • 2021 • Peters plus syndrome mutations affect the function and stability of human β1,3-glucosyltransferase. PMID:34058199

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