Homozygous Mutations in ADAMTS10 and ADAMTS17 Cause Lenticular Myopia, Ectopia Lentis, Glaucoma, Spherophakia, and Short Stature Jose Morales, Latifa.

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Homozygous Mutations in ADAMTS10 and ADAMTS17 Cause Lenticular Myopia, Ectopia Lentis, Glaucoma, Spherophakia, and Short Stature Jose Morales, Latifa Al-Sharif, Dania S. Khalil, Jameela M.A. Shinwari, Prashant Bavi, Rahima A. Al-Mahrouqi, Ali Al-Rajhi, Fowzan S. Alkuraya, Brian F. Meyer, Nada Al Tassan The American Journal of Human Genetics Volume 85, Issue 5, Pages 558-568 (November 2009) DOI: 10.1016/j.ajhg.2009.09.011 Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 1 Family Pedigrees and Clinical Signs (I) The pedigrees of the four families with more than one affected individual. Families A and F show autosomal-recessive inheritance and a WMS-like condition, and families B and E are classical autosomal-recessive WMS families. (II) (A) Slit-lamp photograph of the right eye of patient WMSA-II.2 displaying clear microspherophakia and showing the equator of an apparently smaller-than-normal crystalline lens within a dilated pupil. There is evidence of prior glaucoma surgery, including a peripheral iridectomy and some peripheral iris synechiae. (B) Comparison of a very shallow anterior chamber highlighted by a yellow line outlining the space between the lens and the inner surface of the cornea on patient WMSA-II.5 and a normal deep anterior chamber of her unaffected half-sibling, WMSA-II.1. (C) Stiffness of joints is illustrated by the inability of patient WMSE-II.6 to make a fist; in contrast, patient WMS-D1 (not displayed on pedigrees, but corresponding to patient number five in Table 1) is making a normal full fist. (D) The hands of patient WMSE-II.6 with short, stubby fingers (brachydactyly) in comparison with the normal hands of patient WMSA-II.5. The American Journal of Human Genetics 2009 85, 558-568DOI: (10.1016/j.ajhg.2009.09.011) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 2 ADAMTS17 Mutations in Patients with Autosomal-Recessive WMS-like Syndrome (A) Linkage analysis via the Allegro module reveals a LOD score of 3 on chromosome 15, as indicated by an arrow. (B) Linkage interval of 2.05 Mb as annotated in the Ensembl genome database. (C) Sequence chromatograms of homozygous mutations encountered in ADAMTS17. (I) c.2458_2459insG (p.E820GfsX23) in exon 18. (II) c.1721+1 G > A splice mutation in intron 12. (III) c.760 C > T (Q254X) in exon 4. Arrows point to mutation sites. The American Journal of Human Genetics 2009 85, 558-568DOI: (10.1016/j.ajhg.2009.09.011) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 3 Splicing Patterns of the c.1721 +1 G > A Mutation in ADAMTS17 in Patient WMS-D1 (A) PCR products of cDNA from the patient (P) and a normal control (NC). Two sets of primers were used for the PCR. The patient cDNA gave three PCR products of different sizes with both sets of primers, whereas the NC gave only the wild-type expected product size. (B) The sequence chromatogram of band “c” from PCR using the forward primer confirms exon 12 skipping. An arrow points to the end of exon 11 and the beginning of exon 13. (C) Sequence chromatogram of PCR band “a.” A double-headed arrow points to the end of exon 12 and the beginning of intron 12, and a single-headed arrow points to the end of the “spliced-in” part of intron 12 and the beginning of exon 13. The American Journal of Human Genetics 2009 85, 558-568DOI: (10.1016/j.ajhg.2009.09.011) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 4 Expression of ADAMTS17 in cDNA Libraries Expression of ADAMTS17 in cDNA libraries from different human adult (top panel) and fetal (bottom panel) tissues. (A) An arrow points to a 400 bp ADAMTS17 product specific for isoform “a.” (B) A double-ball-headed arrow indicates a 300 bp ADAMTS17 product specific for isoform “b.” A Single-headed arrow points to a third transcript detected. The American Journal of Human Genetics 2009 85, 558-568DOI: (10.1016/j.ajhg.2009.09.011) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 5 The Two Major Isoforms of the ADAMTS17 Gene Isoform “a” based on Ensembl transcript (ENST00000268070) and isoform “b” is based on Ensembl transcript (ENST00000378898). The protein domains are illustrated, and the position of each of the three mutations is specified. Arrows point to the position of primers flanking exons 4,12, and 18. The American Journal of Human Genetics 2009 85, 558-568DOI: (10.1016/j.ajhg.2009.09.011) Copyright © 2009 The American Society of Human Genetics Terms and Conditions