Novel homozygous, heterozygous and hemizygous FRMD7 gene mutations segregated in the same consanguineous family with congenital X-linked nystagmus

• Published in: European journal of human genetics : EJHG Vol. 20; no. 10; pp. 1032 - 1036
• Main Authors: RADHAKRISHNA, Uppala, RATNAMALA, Uppala, ANTONARAKIS, Stylianos E, DEUTSCH, Samuel, BARTOLONI, Lucia, KURACHA, Murali R, SINGH, Raminder, BANWAIT, Jasjit, BASTOLA, Dhundy K, JOHAR, Kaid, NATH, Swapan K
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.10.2012
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Amino acids; Biological and medical sciences; Case-Control Studies; Child; Codons; Consanguinity; Cytoskeletal Proteins - chemistry; Cytoskeletal Proteins - genetics; Exons; Female; Females; Fundamental and applied biological sciences. Psychology; Genes, X-Linked - genetics; Genetic Diseases, X-Linked - epidemiology; Genetic Diseases, X-Linked - genetics; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Hemizygote; Heterozygote; Homozygote; Humans; India - epidemiology; Male; Medical genetics; Medical sciences; Membrane Proteins - chemistry; Membrane Proteins - genetics; Middle Aged; Missense mutation; Molecular and cellular biology; Mutation; Mutation, Missense - genetics; Nystagmus; Nystagmus, Congenital - epidemiology; Nystagmus, Congenital - genetics; Oculomotor disorders; Open Reading Frames; Ophthalmology; Pedigree; Point mutation; Protein structure; Protein Structure, Secondary; Proteins; Secondary structure; Splice junctions; Studies; X chromosome; India; United States > US; Switzerland; Oklahoma; Sex linked character; Congenital; Family study; Homozygosity; Genetic disease; FRMD7 gene; Eye disease; Gene; mutation analysis; Nystagmus; Genetics; X-Chromosome; Mutation; Oculomotor syndrome
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2012.60

Congenital nystagmus (NYS) is characterized by bilateral, spontaneous, and involuntary movements of the eyeballs that most commonly presents between 2 and 6 months of life. To date, 44 different FRMD7 gene mutations have been found to be etiological factors for the NYS1 locus at Xq26-q27. The aim of this study was to find the FRMD7 gene mutations in a large eleven-generation Indian pedigree with 71 members who are affected by NYS. Mutation analysis of the entire coding region and splice junctions of the FRMD7 gene revealed a novel missense mutation, c.A917G, predicts a substitution of Arg for Gln at codon 305 (Q305R) within exon 10 of FRMD7. The mutation was detected in hemizygous males, and in homozygous and heterozygous states in affected female members of the family. This mutation was not detected in unaffected members of the family or in 100 unrelated control subjects. This mutation was found to be at a highly conserved residue within the FERM-adjacent domain in affected members of the family. Structure prediction and energetic analysis of wild-type FRMD7 compared with mutant (Q305R) revealed that this change in amino acid led to a change in secondary structure predicted to be an energetically unstable protein. The present study represents the first confirmation of FRMD7 gene mutations in a multigenerational Indian family and expands the mutation spectrum for this locus.