Mental Retardation and Abnormal Skeletal Development (Dyggve-Melchior-Clausen Dysplasia) Due to Mutations in a Novel, Evolutionarily Conserved Gene Daniel.

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Mental Retardation and Abnormal Skeletal Development (Dyggve-Melchior-Clausen Dysplasia) Due to Mutations in a Novel, Evolutionarily Conserved Gene Daniel H. Cohn, Nadia Ehtesham, Deborah Krakow, Sheila Unger, Alan Shanske, Kent Reinker, Berkley R. Powell, David L. Rimoin The American Journal of Human Genetics Volume 72, Issue 2, Pages 419-428 (February 2003) DOI: 10.1086/346176 Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 1 Left panel, Lateral view of the spine, showing platyspondyly and the characteristic double-humped appearance of the vertebral bodies with anterior beaking. Right panel, Antero-posterior view of the hips, showing short, widened ilia with a lacy appearance of the iliac crests. The acetabulae are hypoplastic and irregular. The proximal femoral necks are short, with irregular metaphyses and epiphyses. The American Journal of Human Genetics 2003 72, 419-428DOI: (10.1086/346176) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 2 Mutations in DMC. a, Chromatograms showing the mutation in family R94-187 and (below) a normal sequence. The sequence, with the mutant nucleotide and the corresponding normal nucleotide identified with an arrow, is shown above, and the reading frame is underlined. The nucleotide sequence is numbered from the beginning of the coding sequence. The pedigree, demonstrating segregation of the mutation in the family, is shown to the right. b, Chromatograms showing the mutation in family R02-106, together with a normal sequence. An arrow identifies the mutant nucleotide and the corresponding normal nucleotide, and the reading frame is underlined. A vertical line identifies the exon-intron junction. Segregation of the mutation in the family is shown on the pedigree to the right. c, Chromatograms showing the two mutations identified in family R96-219. The reading frame is underlined, and, in each panel, an arrow identifies the normal (above) and mutant (below) sequences. Segregation of the mutations in the family is shown on the pedigree to the right. The American Journal of Human Genetics 2003 72, 419-428DOI: (10.1086/346176) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 3 Comparison of the protein sequences of FLJ90130 and homologous proteins in other species. ClustalW was used for the alignment. The species from which each sequence is derived is shown on the left (M. musculus [Mm], D. melanogaster [Dm], A. gambiae [Ag], C. elegans [Ce], and A. thaliana [At]), and the amino acid residue numbers are shown on the right. Colors are used to indicate classes of amino acid residues, including hydrophobic and aromatic (green), acidic (blue), basic (dark red), and hydrophilic (green) residues. Symbols below the amino acid sequences indicate identity (*), presence of conserved substitutions (:), or presence of semiconserved substitutions (.). A gray background highlights the residues changed by the two identified missense mutations, E87 and N469. The American Journal of Human Genetics 2003 72, 419-428DOI: (10.1086/346176) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 3 Comparison of the protein sequences of FLJ90130 and homologous proteins in other species. ClustalW was used for the alignment. The species from which each sequence is derived is shown on the left (M. musculus [Mm], D. melanogaster [Dm], A. gambiae [Ag], C. elegans [Ce], and A. thaliana [At]), and the amino acid residue numbers are shown on the right. Colors are used to indicate classes of amino acid residues, including hydrophobic and aromatic (green), acidic (blue), basic (dark red), and hydrophilic (green) residues. Symbols below the amino acid sequences indicate identity (*), presence of conserved substitutions (:), or presence of semiconserved substitutions (.). A gray background highlights the residues changed by the two identified missense mutations, E87 and N469. The American Journal of Human Genetics 2003 72, 419-428DOI: (10.1086/346176) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 4 Mutations in SMC. a, Chromatograms showing the two mutations identified in families R94-126 and R98-116. For the E87K mutation, shown above, the reading frame is underlined, and the arrow identifies the normal (above) and mutant (below) sequences. For the exon-skipping mutation, the smaller arrow identifies the normal (above) and mutant (below) sequences. The intron-exon junction is identified with a vertical line and marked with the larger arrow. Segregation of the mutations in each family is shown on the pedigrees to the right. b, Skipping of exon 8 in cartilage RNA from an affected member of each family. On the left, an image of the agarose gel used to separate the amplified cDNA fragments from cartilage of patient II-5 in family R94-126 (“A”) and patient III-2 in family R98-116 (“B”), along with a fragment derived from normal fetal cartilage (“C”). Fragment sizes are indicated to the left. The chromatogram on the right shows the sequence across the exon 7/exon 9 boundary, which is identified by a vertical line, in the shorter cDNA fragment from patient II-5 in family R94-126. The American Journal of Human Genetics 2003 72, 419-428DOI: (10.1086/346176) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 5 Structure of the FLJ90130 protein, with the six predicted transmembrane domains shown in yellow. The beginning and ending residues of each transmembrane segment are indicated. Shown below are the predicted consequences of each mutation on the protein sequence/structure in the three DMC and two SMC families studied. Where the mutation results in a frameshift, the portion of the protein beyond the frameshift is indicated in red. The locations of missense mutations are identified with a dot and the specific protein-sequence change. The American Journal of Human Genetics 2003 72, 419-428DOI: (10.1086/346176) Copyright © 2003 The American Society of Human Genetics Terms and Conditions