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Brian D Perkins, Meghan J Marino, Gayle J T Pauer, John (pei wen) Chiang, Glenn Lobo, Joseph Fogerty, Stephanie A Hagstrom, Elias I Traboulsi; Retinitis Pigmentosa or Sperm Dysfunction as the Only Signs of BBS2 Mutations. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2869.
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© ARVO (1962-2015); The Authors (2016-present)
To describe a family with retinitis pigmentosa (RP) due to BBS2 mutations and to functionally characterize the mutant proteins.
Fundus photographs, visual fields, and OCT images were obtained for the female proband and a male sibling. Molecular analysis via Next Generation Sequencing (NGS) found two BBS2 missense alleles, which were confirmed by Sanger Sequencing. In silico analysis of the mutant alleles was evaluated using Polyphen-2, pMut, and SIFT algorithms. Antisense morpholinos against zebrafish bbs2 were injected into 1-cell embryos and assessed for convergent-extension defects. Embryos were also injected with in vitro synthesized mRNA for wild-type and mutant human BBS2 alleles to test allele function. Protein localization of Bbs2 proteins was examined by immunohistochemistry in transfected HEK293T cells.
A 41 year-old Caucasian female was diagnosed with RP and displayed significant visual field constriction, nyctalopia, and peripheral pigmentary changes, but no systemic problems. Her 39 year-old brother was asymptomatic and had been diagnosed with a low percentage of motile sperm and abnormal sperm morphology when he and his wife were evaluated for infertility. Additional examination showed mild peripheral bone spicule changes in his fundus. NGS analysis found 2 BBS2 variants, a p.R275X pathogenic allele and a p.P134R novel allele, which were determined to be inherited independently from each parent. Both mutant alleles failed to rescue a morpholino knockdown of the zebrafish bbs2 gene. Immunohistochemistry of V5-tagged Bbs2 proteins found that wild-type Bbs2 localized to the basal body, whereas both mutant proteins aggregated away from the cilium.
This family highlights the clinical variability in patients with Bardet-Biedl Syndrome and describes a novel BBS2 mutation. Both mutant alleles are nonfunctional, yet only RP and sperm dysfunction were observed. The results confirm that mutations in BBS2 may cause nonsyndromic recessive RP, and that infertility may be the only problem in patients with mild asymptomatic retinopathy.
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