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Mutations in FRMD7, a Newly Identified Member of the FERM

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Mutations in FRMD7, a Newly Identified Member of the FERM BRIEF COMMUNICATIONS Mutations in FRMD7, a newly pathology, including ocular albinism, congenital stationary night blindness, achromatopsia, blue cone monochromatism and sensory identified member of the FERM visual defects of early childhood such as congenital cataract, retinitis pigmentosa, cone-rod dystrophy and optic nerve hypoplasia4. family, cause X-linked idiopathic ICN is usually inherited as an X-linked trait with incomplete penetrance in females. Most families map to Xq26–q27 and the congenital nystagmus locus (known as NYS1) has previously been mapped to a B12-Mb Patrick Tarpey1,20, Shery Thomas2,20, Nagini Sarvananthan2, interval between markers DXS9909 and DXS1211 (refs. 5,6). Others Uma Mallya3, Steven Lisgo4, Chris J Talbot5, Eryl O Roberts2, have proposed a further reduction of the candidate region to an Musarat Awan2, Mylvaganam Surendran2, Rebecca J McLean2, interval between DXS8033 and DXS8043 based on a recombination 7 Robert D Reinecke6, Andrea Langmann7, Susanne Lindner7, event in a clinically unaffected female . X-linked genetic heterogeneity Martina Koch7, Sunila Jain8, Geoffrey Woodruff2, has been suggested on the basis of a single ICN family that is reported Richard P Gale9, Chris Degg10, Konstantinos Droutsas11, to map to Xp11.4– Xp11.3 (ref. 8). http://www.nature.com/naturegenetics Ioannis Asproudis12, Alina A Zubcov13, Christina Pieh14, We screened 16 families with X-linked ICN using 17 markers 6 Colin D Veal5, Rajiv D Machado15, Oliver C Backhouse9, extending from Xq26–Xq27 (Supplementary Fig. 1 online) .In B Laura Baumber5,15, Cris S Constantinescu16,MichaelCBrodsky17, these families, the disease was fully penetrant in males and 50% David G Hunter18,RichardWHertle19, Randy J Read3, penetrant in females. The phenotype was variable even within families Sarah Edkins1,SarahO’Meara1, Adrian Parker1,ClaireStevens1, (Supplementary Fig. 2 and Supplementary Videos 1, 2 and 3 online). Jon Teague1,RichardWooster1, P Andrew Futreal1, In all 16 families, marker haplotypes were compatible with linkage to Richard C Trembath15, Michael R Stratton1, F Lucy Raymond3 & Xq26–q27 (Supplementary Methods online). Recombinant events in B Irene Gottlob2 affected males in family N1 refined the location of NYS1 to a 7.5-Mb interval between markers DXS1047 and DXS1041 (Fig. 1a,b). Idiopathic congenital nystagmus is characterized by The candidate interval contained 480 genes. We performed high- Nature Publishing Group Group Nature Publishing involuntary, periodic, predominantly horizontal oscillations throughput DNA sequence analysis of all coding exons of all genes 6 of both eyes. We identified 22 mutations in FRMD7 in within this interval9. DNA from one affected male individual from 200 26 families with X-linked idiopathic congenital nystagmus. each of the 16 linked families was screened for mutations. © Screening of 42 singleton cases of idiopathic congenital We detected mutations in FRMD7 (FERM domain–containing 7, nystagmus (28 male, 14 females) yielded three mutations (7%). previously known as LOC90167) at Xq26.2 in 15/16 of the linked We found restricted expression of FRMD7 in human embryonic families after screening 440 genes by sequence analysis (Fig. 1c). brain and developing neural retina, suggesting a specific role in FRMD7 has 12 exons and encodes a previously unidentified member the control of eye movement and gaze stability. of the protein 4.1 superfamily (RefSeq accession number NM_194277). All mutations identified in FRMD7 cosegregated with The prevalence of idiopathic congenital nystagmus (ICN) is estimated disease in the linked families and were absent from 300 male control to be 1 in 1,000. In ICN, visual function can be significantly reduced chromosomes (Table 1). The nonsense mutations leading to Q201X owing to constant eye movement, but the degree of visual impairment and R335X predict truncated proteins containing 28% and 47% of the varies1,2. The disease is likely to be due to abnormal development of protein, respectively. Four of the five splice site mutations were at areas in the brain controlling eye movements and gaze stability3.ICN conserved splice donor residues (position +1 and +2) and are is distinct from other hereditary causes of nystagmus and ocular thus predicted to be pathological by classical exon skipping and 1Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. 2Ophthalmology Group, School of Medicine, University of Leicester, PO Box 65, Leicester LE2 7LX, UK. 3Cambridge Institute for Medical Research, Addenbrookes Hospital, Cambridge CB2 2XY, UK. 4Institute of Human Genetics, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 7RU, UK. 5Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK. 6Foerderer Eye Movement Centre for Children, Wills Eye Hospital, Philadelphia, Pennsylvania 19107, USA. 7Medical University Graz, Department of Ophthalmology, Auenbruggerplatz 4, 8036 Graz, Austria. 8Royal Preston Hospital, Sharoe Green Lane North, Fulwood, Preston, Lancashire PR2 9HT, UK. 9Department of Ophthalmology, Leeds General Infirmary, Leeds LS2 9NS, UK. 10Department of Medical Physics, University Hospitals of Leicester, Leicester LE1 5WW, UK. 11Department of Ophthalmology, Justus- Liebig-University, 35392 Giessen, Germany. 12Department of Ophthalmology, Medical Faculty, University Hospital of Ioannina, 45110 Ioannina, Greece. 13University Eye Hospital, Johann-Wolfgang-Goethe-Universita¨t, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany and Ginnheimer Hohl 6, 60431 Frankfurt/Main, Germany. 14Ophthalmology Department, University of Freiburg, Freiburg, Germany. 15Division of Genetics and Molecular Medicine, King’s College London SE1 9RT, UK. 16Division of Clinical Neurology, School of Medical and Surgical Sciences, University of Nottingham, Nottingham NG7 2UH, UK. 17Departments of Ophthalmology and Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202, USA. 18Department of Ophthalmology, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA. 19University of Pittsburgh Medical Centre, Division of Paediatric Ophthalmology, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA. 20These authors contributed equally to this work. Correspondence should be addressed to F.L.R. (fl[email protected]) or I.G. ([email protected]). Received 6 June; accepted 1 September; published online 1 October 2006; doi:10.1038/ng1893 1242 VOLUME 38 [ NUMBER 11 [ NOVEMBER 2006 NATURE GENETICS BRIEF COMMUNICATIONS missense mutations in FRMD7 except the a l lI one leading to Y301C in the linked families. lII We inspected the structural environment of lV the disease-associated missense mutations V d e using the program Coot, which allows the VI N1 v identity and conformation of residues to be 12 c 130.1 Mb manipulated easily . Although the effect on DXS8072 cp the structure of L231V is not clearly apparent, v 130.8 mutations leading to G24R, L142R and C271 r are likely to destabilize the protein by the b 130.9 introduction of larger amino acids within V2 VI2 IV9 MST DXS1047 199 199 203 DXS8072 222 222 222 fgh restricted areas of the protein, and the intro- DXS8071 199 199 199 r DXS6748 211 211 211 LOC90167 DXS1114 114 114 144 131 duction of a proline residue at position 266 DXS8041 155 115 115 DXS8033 258 258 258 (A266P) will disrupt a helical domain in the DXS134.1 243 243 243 h DXS134.2 157 157 157 RAP2C DXS134.6 207 207 207 131.1 wild-type structure. DXS134.9 216 216 216 cp DXS691 155 155 155 From the results above, we concluded that GDB:204469 246 246 DXS8071 DXS8094 235 235 235 s DXS1041 169 157 169 mutations in FRMD7 are a major cause of DXS8050 197 199 197 131.2 DXS998 114 114 114 familial X-linked congenital motor nystag- MBNL3 mus. We then assessed the prevalence of 131.3 mutations in FRMD7 in smaller families in Figure 1 Refinement of the linkage interval to Xq26 and the pattern of expression of FRMD7 in brain which linkage data was not available and in a of human embryos B56 d.p.o. by in situ hybridization. (a) Pedigree of family N1. Arrow marks critical cohort of males and females with ICN but http://www.nature.com/naturegenetics individuals whose haplotypes define the minimum critical linkage interval. (b) Allele size for marker without a family history of the condition. We DXS1047 in individual IV9 is discordant compared with the other affected males, V2 and VI2, and the screened 14 families with two or more allele size at markers DXS1041 and DXS8050 in individual VI2 is discordant compared with affected individuals of either sex and found individuals V2 and IV9. (c) Location of LOC90167 (FRMD7) relative to the linkage markers DXS8072 mutations in 8/14 (57%). We also identified and DXS8071.(d–h) A 599-bp and a 681-bp probe from unique sequence in the 3¢ UTR of FRMD7 were used as probes for in situ hybridization. d and f show in situ hybridization results using sense mutations in 3/42 (7%) individuals without a probes, and e and g use antisense probes in similar anatomical locations. d and e are sagittal sections family history who had undergone careful showing the lateral ventricle (v), cerebellar peduncle (cp) and developing neural retina (r). h is an clinical and electrophysiological investigation enlargement of e, illustrating the retina. f and g are transverse sections showing the spinal cord (s), to exclude other causes of inherited congeni- hypothalamus (h) and cerebellar peduncle (cp). Scale bars: e, 2,000 mm; g, 1,800 mm. The study was tal nystagmus (Table 1). We identified muta- approved by the University of Leicester Ethics Committee. Written informed consent was obtained from tions in 1/14 female singletons and 2/28 male all study participants. singletons, and none of the new mutations Nature Publishing Group Group Nature Publishing 6 was found in samples from 300 male control nonsense-mediated decay. In family N7, whose members had the individuals. The results suggest that mutation analysis of FRMD7 may 200 - © mutation IVS2 +5G A, we detected negligible amounts of transcript be considered of diagnostic value even in isolated cases of either sex.
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