A novel H395R mutation in MKKS/BBS6 causes retinitis pigmentosa and polydactyly without other findings of Bardet-Biedl or McKusick-Kaufman syndrome

Mol Vis. 2016 Jan 24;22:73-81. eCollection 2016.

Abstract

Purpose: To identify the causative mutation in two siblings from a consanguineous family in India with retinitis pigmentosa (RP) and polydactyly without other findings of Bardet-Biedl syndrome (BBS). We also performed functional characterization of the mutant protein to explore its role in this limited form of BBS.

Methods: The siblings underwent a thorough ophthalmological examination, including retinal optical coherence tomography (OCT) imaging, and an extensive physical examination with abdominal ultrasonography to characterize the disease phenotype. Next-generation sequencing (NGS) using a panel targeting retinal degeneration genes was performed on genomic DNA samples from the siblings and parents. Upon identification of the causative mutation, functional characterization was accomplished by performing protein-protein interaction studies in human embryonic kidney (HEK-293T) and human adult retinal pigmented epithelium (ARPE-19) cells.

Results: The two siblings showed signs of RP and polydactyly. The patients did not have truncal obesity, renal anomalies, hydrometrocolpos, congenital heart disease, or overt cognitive defects. NGS identified a homozygous c.1184A>G mutation in the MKKS/BBS6 gene in both patients resulting in a p.H395R substitution in the MKKS/BBS6 protein. This mutant protein decreased the interaction of MKKS/BBS6 with BBS12 but did so to a different extent in the HEK-293T versus ARPE-19 cells. Nonetheless, the effect of the H395R variant on disrupting interactions with BBS12 was not as profound as other reported MKKS/BBS6 mutations associated with syndromic RP.

Conclusions: We identified a novel H395R substitution in MKKS/BBS6 that results in a unique phenotype of only RP and polydactyly. Our observations reaffirm the notion that mutations in MKKS/BBS6 cause phenotypic heterogeneity and do not always result in classic MKKS or BBS findings.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Adolescent
  • Bardet-Biedl Syndrome / genetics*
  • Blotting, Western
  • Consanguinity
  • DNA Mutational Analysis
  • Female
  • Group II Chaperonins / genetics*
  • HEK293 Cells
  • Heart Defects, Congenital / genetics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hydrocolpos / genetics*
  • Male
  • Mutation, Missense*
  • Pedigree
  • Plasmids
  • Polydactyly / genetics*
  • Retinal Pigment Epithelium / cytology
  • Retinitis Pigmentosa / genetics*
  • Siblings
  • Tomography, Optical Coherence
  • Uterine Diseases / genetics*

Substances

  • MKKS protein, human
  • Group II Chaperonins

Supplementary concepts

  • McKusick Kaufman syndrome