title: A novel H395R mutation in MKKS/BBS6 causes retinitis pigmentosa and polydactyly without other findings of Bardet-Biedl or McKusick-Kaufman syndrome.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: John D
authors.initials: JD
authors.lastname: Hulleman
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Annie
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: MedGenome, Bangalore, Karnataka, India.
authors.forename: V L
authors.initials: VL
authors.lastname: Ramprasad
authors.affiliation: MedGenome, Bangalore, Karnataka, India.
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Murugan
authors.affiliation: MedGenome, Bangalore, Karnataka, India.
authors.forename: Ravi
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Srikiran Institute of Ophthalmology, Kakinada, Andhra Pradesh, India.
authors.forename: Avinash
authors.initials: A
authors.lastname: Mahindrakar
authors.affiliation: Sai Sudha Hospital, Kakinada, Andhra Pradesh, India.
authors.forename: Ravi
authors.initials: R
authors.lastname: Angara
authors.affiliation: Srikiran Institute of Ophthalmology, Kakinada, Andhra Pradesh, India.
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Sankurathri
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX; Srikiran Institute of Ophthalmology, Kakinada, Andhra Pradesh, India; McDermott Center for Human Growth and Development/Center for Human Genetics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: V Vinod
authors.initials: VV
authors.lastname: Mootha
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D020788:Bardet-Biedl Syndrome / Q000235:genetics*; D015153:Blotting, Western; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D056385:Group II Chaperonins / Q000235:genetics*; D057809:HEK293 Cells; D006330:Heart Defects, Congenital / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D052202:Hydrocolpos / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010957:Plasmids; D017689:Polydactyly / Q000235:genetics*; D055213:Retinal Pigment Epithelium / Q000166:cytology; D012174:Retinitis Pigmentosa / Q000235:genetics*; D035781:Siblings; D041623:Tomography, Optical Coherence; D014591:Uterine Diseases / Q000235:genetics*
chemical_list: C414726:MKKS protein, human; D056385:Group II Chaperonins