Mutations in CABP4, the Gene Encoding the Ca2+-Binding Protein 4, Cause Autosomal Recessive Night Blindness Christina Zeitz, Barbara Kloeckener-Gruissem,

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Mutations in CABP4, the Gene Encoding the Ca2+-Binding Protein 4, Cause Autosomal Recessive Night Blindness Christina Zeitz, Barbara Kloeckener-Gruissem, Ursula Forster, Susanne Kohl, István Magyar, Bernd Wissinger, Gábor Mátyás, François- Xavier Borruat, Daniel F. Schorderet, Eberhart Zrenner, Francis L. Munier, Wolfgang Berger The American Journal of Human Genetics Volume 79, Issue 4, Pages 657-667 (October 2006) DOI: 10.1086/508067 Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 1 The different forms of human CSNB are classified according to their mode of inheritance, phenotype, and mutated genes. ad = Autosomal dominant; ar = autosomal recessive; cCSNB = complete CSNB; icCSNB = incomplete CSNB. Genes are indicated in italics and are underlined. Chromosomal location is given in parentheses. The American Journal of Human Genetics 2006 79, 657-667DOI: (10.1086/508067) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 2 Pedigrees of two families with arCSNB and segregating mutations. A, Pedigree of family A. B, Pedigree of family B. Circles indicate females, squares indicate males, open symbols indicate unaffected individuals, semifilled symbols indicate carriers, and filled symbols indicate affected individuals. Generations and individuals are identified by roman and arabic numerals, respectively. The determined genotype is given below each symbol. C, Electropherograms showing two different CABP4 mutations. Arrows indicate the site of mutation. Patients II-5 and II-6 of family A were homozygous for c.800_801delAG, whereas patient II-1 of family B was compound heterozygous for the missense mutation c.370C→T and for the c.800_801delAG deletion. Lowercase letters indicate intronic sequences, and uppercase letters indicate exonic sequences. The American Journal of Human Genetics 2006 79, 657-667DOI: (10.1086/508067) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 3 ERG profile of the patients with CSNB investigated. A–D, Full-field ERG of family A. Results of an unaffected representative subject are shown in the left column. Results from patients II-5 and II-6 are shown in the middle and right columns, respectively. The upper line represents the right eye, the lower line the left eye. A, Scotopic ISCEV standard flash (2.5 candelas [cd]/m2) attenuated by 24 dB. Moderately decreased amplitude and delayed culmination time of the b-wave were present in both patients. B, Scotopic standard flash. Normal a-wave amplitude and implicit time with an absent b-wave (negative ERG) was present in both patients. C, Photopic ISCEV standard flash (30 cd/m2). Decreased amplitude of both a- and b-waves with normal implicit times was present in both patients. D, Photopic 30-Hz flicker stimulus. Decreased b-wave amplitude with normal implicit time was present in both patients. E, Full-field ERG of index patient of family B. OD = right eye; OS = left eye. Top panel, Scotopic ERG. Uppermost trace indicates ERG elicited by ISCEV standard flash (2.5 cd/m2) attenuated by 24 dB, with highly decreased amplitude and delayed culmination time of the b-wave (3 and 9 ms above upper norm for OD and OS, respectively). Middle trace indicates unattenuated scotopic ISCEV standard flash, with normal a-wave amplitude and implicit time with an absent b-wave (negative ERG). Lower trace indicates a repeat of the same conditions as used in the second trace. Bottom panel, Photopic ERG. Upper trace indicates white background light (30 cd/m2) with ISCEV standard flash stimulus and decreased amplitude of both a- and b-waves with delayed implicit time 3 ms above upper norm value; the wavelets toward the end of this trace are blink artifacts in both eyes. Lower trace indicates photopic 30-Hz flicker stimulus with highly decreased amplitude and normal implicit time. The American Journal of Human Genetics 2006 79, 657-667DOI: (10.1086/508067) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 4 Sequence alignment of normal CABP4 protein and the two mutant variants. Gray boxes indicate the four predicted Ca2+-binding EF hand motifs; however, EF2 was predicted to be nonfunctional.29 Red letters show the mutated amino acids and the elongated residues. The missense mutation is marked by an arrow. Bold letters highlight known and predicted phosphorylation sites. The American Journal of Human Genetics 2006 79, 657-667DOI: (10.1086/508067) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 5 CABP4 transcript analysis. A, Structure of the CABP4 gene. Boxed symbols represent exons; lines represent introns. Arrows indicate the position of primers used for RT-PCR experiments; the caret indicates the position of the TaqMan probe; dotted lines indicate two mutations in CABP4, c.370C→T and c.800_801delAG. B–D, Ethidium bromide– and GelRed-stained agarose gels with RT-PCR fragments. B, Primers from CABP4 exons 2 and 6. C, Primers from CABP4 exons 2 and 4. D, Primers from CSPG2 exons 6 and 9. E, Relative expression of CABP4 transcripts from quantitative real-time RT-PCR experiments with the use of TaqMan probes. Threshold-cycle values ranged from 19 to 22 for samples probed with 18S rRNA and from 29 to 33 for samples probed with CABP4. Bars represent CIs; P=.05. The American Journal of Human Genetics 2006 79, 657-667DOI: (10.1086/508067) Copyright © 2006 The American Society of Human Genetics Terms and Conditions