Homozygosity for a Missense Mutation in SERPINH1, which Encodes the Collagen Chaperone Protein HSP47, Results in Severe Recessive Osteogenesis Imperfecta

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1 Chapter 16 SERPINH1 and Osteogenesis Imperfecta Copyright © 2014 Elsevier Inc. All rights reserved.

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Homozygosity for a Missense Mutation in SERPINH1, which Encodes the Collagen Chaperone Protein HSP47, Results in Severe Recessive Osteogenesis Imperfecta Helena E. Christiansen, Ulrike Schwarze, Shawna M. Pyott, Abdulrahman AlSwaid, Mohammed Al Balwi, Shatha Alrasheed, Melanie G. Pepin, Mary Ann Weis, David R. Eyre, Peter H. Byers The American Journal of Human Genetics Volume 86, Issue 3, Pages 389-398 (March 2010) DOI: 10.1016/j.ajhg.2010.01.034 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 X-Rays Radiographs of the skull at age 1 year (A) demonstrate diminished calvarial mineralization and enlargement of the calvarial vault. At birth, the chest (B) was small, the ribs were thin and some had healing fractures, one clavicle was bent, both humeral bones had fractures, platyspondyly was present, and overall mineralization appeared diminished. By 1 year of age (C and D), the ribs had become broad, platyspondyly was still apparent with diminished central mineralization of the vertebral bodies, and the humeral bones had a tubular shape, thin cortices, and diminished mineralization. The deformity and decreased mineralization of the bones in the arms are apparent at 1 year (E), and the minimal effect of pamidronate can be seen. At 1 month (F), 1 year (G), and 28 months (H), there is rhizomelic shortening and limited modeling of the long bones with very thin cortices. The lines of increased mineralization reflect the successive pamidronate infusions. The American Journal of Human Genetics 2010 86, 389-398DOI: (10.1016/j.ajhg.2010.01.034) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Identification of a Homozygous Mutation in SERPINH1 (A) Family pedigree with consanguineous heterozygous parents (III-2 and III-3) and affected proband (IV-1, black arrow). Asterisks indicate individuals studied. (B) Homozygous c.233T>C, p.Leu78Pro mutation in exon 1 of SERPINH1 in proband, IV-1 (red box). Parents (III-2 and III-3) were heterozygous at this site. (C) The completely conserved 16 amino acid sequence in HSP47 that contains the leucine-to-proline substitution. The American Journal of Human Genetics 2010 86, 389-398DOI: (10.1016/j.ajhg.2010.01.034) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 3 Mutation of SERPINH1 Generates an Unstable Protein (A) PCR amplification of cDNA (35 cycles for each) from control (C) and from patient (IV-1) showed that the mRNA for SERPINH1 was stable. (B) Western blot analysis indicated that HSP47 was significantly decreased in patient cells (IV-1). (C) Immunocytochemistry with antibodies to HSP47 and the ER marker protein disulfide isomerase (PDI) showed a normal ER distribution of HSP47 in control cells and a severe reduction in HSP47 in patient cells (IV-1). The merged image (right column) confirms the absence of staining for HSP47. (D) Western blot showed partial rescue of HSP47 beginning at ∼8 hr of treatment with proteasome inhibitor MG-132. (E) HSP47 was stabilized after treatment of cells with cycloheximide (CHX) and MG-132 but in the absence of MG-132, even with continuous presence of CHX, previously stabilized HSP47 was destroyed. The American Journal of Human Genetics 2010 86, 389-398DOI: (10.1016/j.ajhg.2010.01.034) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 4 Type I Procollagen Synthesis and Secretion (A) Labeling of cells with [3H]-proline for 16 hr showed normal synthesis and secretion of type I procollagen into the culture medium and normal electrophoretic mobilities of the constituent chains. The chains of the procollagens were separated under reducing conditions. The collagens represent the procollagens after digestion with pepsin and electrophoresis under nonreducing conditions. (B) Cells were labeled for 1 hr with [3H]-proline then chased for up to 2 hr with unlabeled proline. The secretion of the trimers of type I procollagen showed a delay in the rate of secretion in the patient cells, quantitated in the graph to the right. The American Journal of Human Genetics 2010 86, 389-398DOI: (10.1016/j.ajhg.2010.01.034) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 5 Type I Collagen Accumulates in the Golgi of HSP47 Mutant Cells Immunocytochemistry with antibodies against the N-propeptide of proα1(I), Golgi marker 58K Golgi protein, and ER marker KDEL showed localization of type I procollagen to both Golgi and ER in control cells. In patient cells (IV-1 rows), type I procollagen was diminished in the ER and accentuated in the Golgi. The American Journal of Human Genetics 2010 86, 389-398DOI: (10.1016/j.ajhg.2010.01.034) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 6 Mutation of HSP47 Affects Protease Sensitivity and Thermostability of the Type I Collagen Triple Helix (A) Proteins in medium from cultured dermal fibroblasts labeled overnight with [3H]-proline were digested for 1 or 5 min with a combination of trypsin and chymotrypsin at 37°C without prior cooling of the sample. Pepsin-treated samples were ethanol precipitated at 4°C and then digested for 2 hr at 16°C. Procollagens secreted into the culture medium by control cells and then pretreated at 50°C for 15 min showed complete degradation after treatment with trypsin/chymotrypsin while procollagens from medium left at 37°C had protease-resistant triple helical domains. A subset of type I procollagen molecules secreted from patient cells were cleaved asymmetrically at 37°C (the black arrows indicate fragments seen in affected cells and either not seen or in low abundance in the control cells). (B) Characterization by cyanogen bromide peptide mapping of the cleavage products of type I procollagen after trypsin/chymotrypsin treatment. The gel lanes from runs equivalent to those in (A) were excised and the bands cleaved with cyanogen bromide. The larger of the new bands, which migrated just below α2(I), was derived from α1(I). The CB7 fragment is missing and replaced by fragment A. The size of the fragment indicates that the parent peptide had been cleaved in CB7 near the mammalian collagenase cleavage site (775–776 in the triple helical domain). The smaller fragment in the parent gel was derived from α2(I). The CB3-5 fragment was shortened, fragment B, and the estimated size indicated that it had been cleaved in the region of the collagenase cleavage site. (C) Thermal stability of type I collagen molecules. Cells were incubated overnight with [3H]-proline in the presence of sodium ascorbate (50 μg/ml). The secreted proteins were collected by precipitation with ethanol and then reheated to the temperatures shown at which point they were treated with trypsin/chymotrypsin for 2 min. The thermostability of type I collagen was increased in patient cells by about 0.5°C (∗). The American Journal of Human Genetics 2010 86, 389-398DOI: (10.1016/j.ajhg.2010.01.034) Copyright © 2010 The American Society of Human Genetics Terms and Conditions