PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy.

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PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy Syndrome Anil K. Agarwal, Chao Xing, George N. DeMartino, Dario Mizrachi, Maria Dolores Hernandez, Ana Berta Sousa, Laura Martínez de Villarreal, Heloísa G. dos Santos, Abhimanyu Garg The American Journal of Human Genetics Volume 87, Issue 6, Pages 866-872 (December 2010) DOI: 10.1016/j.ajhg.2010.10.031 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Homozygous Region Shared by Affected Individuals with JMP Syndrome, Position of Candidate Genes in the Region, Structure of PSMB8, and Disease-Causing Mutation (A) Homozygous region shared by the affected individuals JMP 200.4, 200.3, and 100.3. The B allele frequency is a normalized measure of the allelic intensity ratio of the two alleles, and deviation from 0.5 indicates homozygosity. The genomic position is based on NCBI36/hg18 assembly. Each dot indicates the SNP genotyped by means of the Illumina HumanOmni1-Quad Beadchip. The vertical lines for each panel indicate the regions of homozygosity. Isolated heterozygous SNPs within larger homozygous segments are likely to represent miscalls. (B) Position of some of the candidate genes in the critical region identified by homozygosity mapping. Tel, telomeric end; cent, centromeric end. The critical region spanned from 31.5 Mb to 34.0 Mb on chromosome 6. (C) Structure of PSMB8 and the location of the mutation in the JMP patients. Human PSMB8 contains six exons and five introns. Also shown are the alternatively spliced exons 1A and 1B. The mutation c.224C>T in PSMB8 is located in exon 2. (D) Sequence electropherogram for normal sequence in exon 2 of PSMB8. (E) Sequence from JMP 200.2 showing heterozygous c.224C>T mutation. (F) Sequence from JMP 200.3 showing the homozygous c.224C>T mutation. The amino acid substitution is shown below the electropherogram. The American Journal of Human Genetics 2010 87, 866-872DOI: (10.1016/j.ajhg.2010.10.031) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Conservation of the Mutated Residue across Species, Crystal Structure of Normal and Mutant PSMB8, Proteasomal Activity, and Expression of β5i in Cell Lysates of Lymphoblasts from an Affected Patient (A) Alignment of partial PSMB8 amino acid sequence around threonine at position 75 in human (NP_683720.2), chimpanzee (XP_001167272.1), dog (XP_532100.1), cow (NP_001035570.1), mouse (NP_034854.1), and zebrafish (NP_571467.2). The conserved residue threonine is highlighted in yellow. Amino acids that are not conserved are shown in red. (B) Protein model for the wild-type and mutant, Thr75Met, human PSMB8. β sheets are shown in blue, helices in orange, and unstructured loops in gray. Threonine 73 and glycine 119 are the catalytic amino acids. Mutation of threonine 75 to methionine widens the distance between the catalytic threonine 73 and glycine 119 by 1.2 Å. All amino acids are numbered according to transcript 1B. (C) Proteasomal activity in EBV-transformed lymphoblasts from a control and an affected patient (JMP200.4). The chymotrypsin-like, trypsin-like, and PGPH-like proteolytic activities are expressed as fluorogenic units (F.U.) per μg of protein. Each bar represents mean ± SD from three independent experiments carried out in duplicate. p values were derived from the paired t test. (D) Western blots. Total cell lysates from EBV-transformed lymophoblasts of a control subject and an affected patient (JMP200.4) were resolved on 10% SDS-PAGE and probed with antibodies against Rpt2 (an ATPase of the PA700, a 19S proteasome regulatory particle), Rpn12 (a subunit of 19S proteasome regulatory subunit), α2, β5i, and β5 (subunits of 20S proteasome), and a housekeeping protein actin. The first two lanes on the left contain purified 20S and PA700 proteins from bovine red blood cells as positive controls. The control and the patient contained the same amount of β5i protein. The American Journal of Human Genetics 2010 87, 866-872DOI: (10.1016/j.ajhg.2010.10.031) Copyright © 2010 The American Society of Human Genetics Terms and Conditions