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

• Published in: Molecular vision 2016-01, Vol.22, p.73-81
• Main Authors: Hulleman, John D, Nguyen, Annie, Ramprasad, V L, Murugan, Sakthivel, Gupta, Ravi, Mahindrakar, Avinash, Angara, Ravi, Sankurathri, Chandrasekhar, Mootha, V Vinod
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - genetics; Adolescent; Bardet-Biedl Syndrome - genetics; Blotting, Western; Consanguinity; DNA Mutational Analysis; Female; Group II Chaperonins - genetics; Heart Defects, Congenital - genetics; HEK293 Cells; 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
• ISSN: 1090-0535; 1090-0535

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. 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. 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. 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.