X-Linked Late-Onset Sensorineural Deafness Caused by a Deletion Involving OA1 and a Novel Gene Containing WD-40 Repeats Maria T. Bassi, Rajkumar S. Ramesar,

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X-Linked Late-Onset Sensorineural Deafness Caused by a Deletion Involving OA1 and a Novel Gene Containing WD-40 Repeats Maria T. Bassi, Rajkumar S. Ramesar, Barbara Caciotti, Ingrid M. Winship, Alessandro De Grandi, Mirko Riboni, Philip L. Townes, Peter Beighton, Andrea Ballabio, Giuseppe Borsani The American Journal of Human Genetics Volume 64, Issue 6, Pages 1604-1616 (June 1999) DOI: 10.1086/302408 Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 1 Genomic structure of TBL1. The orientation of TBL1 with respect to OA1 is shown (top). The number on the top indicates the distance between the two 3′ ends of the genes. The thin bars in the middle denote the cosmid, and are not drawn to scale. Shown at the bottom is the genomic structure of TBL1. Dot-filled squares denote untranslated exons, whereas blackened squares denote coding exons. TEL = telomere and CEN = centromere. The American Journal of Human Genetics 1999 64, 1604-1616DOI: (10.1086/302408) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 2 a, Multiple sequence alignment obtained using the Clustal-W algorithm. TBL1 = human TBL1 polypeptide; DROME = predicted D. melanogaster protein encoded by P1 clone DS05054, P38262 = hypothetical yeast 59.1-kd protein (accession number P38262). Identical and conserved amino acid residues are boxed in dark and light gray, respectively. Numbering is not reported for the D. melanogaster protein, because the complete polypeptide could not be predicted from the currently available genomic sequences. The missing amino acid residues, as well as the gaps inserted by the Clustal-W program, are denoted by dashed lines. b, Position of WD-40 repeats in the TBL1 gene, determined by the HMM search against PFAM. Scores are expressed in bits (LOD score, in base 2); a score >15 is almost always considered significant. The amino acid alignment to the consensus sequence of G-β–transducin (WD-40) repeats is shown to the left for each domain. The American Journal of Human Genetics 1999 64, 1604-1616DOI: (10.1086/302408) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 3 Northern blot analysis of TBL1. The cDNA probe AR145 was hybridized to three commercial northern blots (Clontech) containing 2 μg poly-(A)+ RNA from various human adult (a and b) and fetal (c) tissues. The TBL1 gene is ubiquitously expressed, with two transcripts of ∼2.1 kb and 6.0 kb. In fetal tissues the smaller transcript seems to be more abundant than the larger one. The American Journal of Human Genetics 1999 64, 1604-1616DOI: (10.1086/302408) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 4 A, Tbl1 expression in a mouse cochlea cDNA library, as detected by PCR (see Material and Methods). The positive control R4 represents a clone obtained from a mouse retina cDNA library. B, Inactivation status of TBL1. Oligonucleotide primers from the 3′ UTR region of TBL1 and from the human PGK1 and MIC2 genes were used for the RT-PCR amplification of hamster/human cell hybrids retaining the human active (Xa) or inactive (Xi) X chromosome. Ha = parent hamster line (a plus sign [+] and a minus sign [−] indicate the presence or absence of reverse transcriptase [RT] in the RT reaction, respectively); Hu = human genomic DNA; H2O = no DNA added; and Mw = molecular-weight marker. A 341-bp PCR product was observed in samples from both the active and the inactive X hybrids, indicating that TBL1 escapes X-chromosome inactivation. The American Journal of Human Genetics 1999 64, 1604-1616DOI: (10.1086/302408) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 5 Schematic deletion map surrounding the TBL1 locus. Heavy bars represent the portion of the X chromosome still present in the patient, whereas dashed lines indicate either X-Y translocation (patient BA127) or microinterstitial deletion (patients BA199, BA163, BA126). The entire genomic region is not drawn to scale. KAL = Kallmann syndrome 1 gene, TBL1 = transducin β–like 1, OA1 = X-linked ocular albinism gene, APXL = apical protein from xenopus-like, and CLCN4 = voltage-gated chloride channel 4. Patients' clinical phenotypes are shown on the left, as follows: SS = short stature, CDPX = X-linked chondrodysplasia punctata, MRX = nonspecific mental retardation, XLI = X-linked ichthyosis, KAL = Kallmann syndrome; OASD = ocular albinism with late-onset sensorineural deafness, and OA1 = ocular albinism of the Nettleship-Falls type. TEL = telomere and CEN = centromere. The American Journal of Human Genetics 1999 64, 1604-1616DOI: (10.1086/302408) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 6 A, Pedigree of OASD family. Asterisks (*) indicate the DNA samples analyzed in B. Arrows indicate the proband and the carrier mother whose PCR products were sequenced (see fig. 7). B, Segregation of the deletion breakpoint–containing fragment, as detected by PCR on genomic DNA in all affected males, carrier females, and normal controls (C). H2O = no DNA added. The numbers at the top of the lanes indicate the generation number and the individual number, respectively. The American Journal of Human Genetics 1999 64, 1604-1616DOI: (10.1086/302408) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 7 Localization of the chromosomal breakpoint in a patient with OASD, and schematic representation of a submicroscopic deletion in the patient and nucleotide sequence of the junction fragment. The size of the deleted region and the position of the 12intfl (intron 12 of TBL1) and 6int (intron 6 of OA1) primers used for the amplification are shown (top). Primer sequences are as follows: 12intfl, 5′-GTGCAAGAAGTGTCACGGAG; and 6int, 5′-AGACTGTGCTAGGTGCCCTT. Unblackened squares denote the exons of both genes deleted in the patient, whereas blackened squares denote the deleted ones. The size of the amplification product in the patient (middle) and the sequence of the junction fragment at the breakpoint (bottom) are shown. The dinucleotide TT, present at the breakpoint, is denoted by an unblackened square. TEL = telomere and CEN = centromere. The American Journal of Human Genetics 1999 64, 1604-1616DOI: (10.1086/302408) Copyright © 1999 The American Society of Human Genetics Terms and Conditions