Schimke immunoosseous dysplasia

Suggestions of genetic diversity

J. Marietta Clewing, Helen Fryssira, David Goodman, Sarah F. Smithson, Emily A. Sloan, Shu Lou, Yan Huang, Kunho Choi, Thomas Lücke, Harika Alpay, Jean Luc André, Yumi Asakura, Nathalie Biebuyck-Gouge, Radovan Bogdanovic, Dominique Bonneau, Caterina Cancrini, Pierre Cochat, Sandra Cockfield, Laure Collard, Isabel Cordeiro & 41 others Valerie Cormier-Daire, Karlien Cransberg, Karel Cutka, Georges Deschenes, Jochen H H Ehrich, Stefan Fründ, Helen Georgaki, Encarna Guillen-Navarro, Barbara Hinkelmann, Maria Kanariou, Belde Kasap, Sara Sebnem Kilic, Guiliana Lama, Petra Lamfers, Chantal Loirat, Silvia Majore, David Milford, Denis Morin, Nihal Özdemir, Bertram F. Pontz, Willem Proesmans, Stavroula Psoni, Herbert Reichenbach, Silke Reif, Cristina Rusu, Jorge M. Saraiva, Onur Sakallioglu, Beate Schmidt, Lawrence Shoemaker, Sabine Sigaudy, Graham Smith, Flora Sotsiou, Natasa Stajic, Anja Stein, Asbjørg Stray-Pedersen, Doris Taha, Sophie Taque, Jane Tizard, Michel Tsimaratos, Newton A C S Wong, Cornelius F. Boerkoel

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCALl mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.

Original languageEnglish
Pages (from-to)273-283
Number of pages11
JournalHuman Mutation
Volume28
Issue number3
DOIs
Publication statusPublished - Mar 2007

Fingerprint

Chromatin
Actins
Mutation
Multifactorial Inheritance
Haplotypes
Osteochondrodysplasias
Endophenotypes
Focal Segmental Glomerulosclerosis
Schimke immunoosseous dysplasia
Genetic Association Studies
Epigenomics
Sucrose
Exons
Proteins
Alleles
RNA
T-Lymphocytes
Phenotype
Cell Line
Messenger RNA

Keywords

  • Genocopy
  • Immunodeficiency
  • Locus heterogeneity
  • Proteinuria
  • Skeletal dysplasia
  • SMARCAL1

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Clewing, J. M., Fryssira, H., Goodman, D., Smithson, S. F., Sloan, E. A., Lou, S., ... Boerkoel, C. F. (2007). Schimke immunoosseous dysplasia: Suggestions of genetic diversity. Human Mutation, 28(3), 273-283. https://doi.org/10.1002/humu.20432

Schimke immunoosseous dysplasia : Suggestions of genetic diversity. / Clewing, J. Marietta; Fryssira, Helen; Goodman, David; Smithson, Sarah F.; Sloan, Emily A.; Lou, Shu; Huang, Yan; Choi, Kunho; Lücke, Thomas; Alpay, Harika; André, Jean Luc; Asakura, Yumi; Biebuyck-Gouge, Nathalie; Bogdanovic, Radovan; Bonneau, Dominique; Cancrini, Caterina; Cochat, Pierre; Cockfield, Sandra; Collard, Laure; Cordeiro, Isabel; Cormier-Daire, Valerie; Cransberg, Karlien; Cutka, Karel; Deschenes, Georges; Ehrich, Jochen H H; Fründ, Stefan; Georgaki, Helen; Guillen-Navarro, Encarna; Hinkelmann, Barbara; Kanariou, Maria; Kasap, Belde; Kilic, Sara Sebnem; Lama, Guiliana; Lamfers, Petra; Loirat, Chantal; Majore, Silvia; Milford, David; Morin, Denis; Özdemir, Nihal; Pontz, Bertram F.; Proesmans, Willem; Psoni, Stavroula; Reichenbach, Herbert; Reif, Silke; Rusu, Cristina; Saraiva, Jorge M.; Sakallioglu, Onur; Schmidt, Beate; Shoemaker, Lawrence; Sigaudy, Sabine; Smith, Graham; Sotsiou, Flora; Stajic, Natasa; Stein, Anja; Stray-Pedersen, Asbjørg; Taha, Doris; Taque, Sophie; Tizard, Jane; Tsimaratos, Michel; Wong, Newton A C S; Boerkoel, Cornelius F.

In: Human Mutation, Vol. 28, No. 3, 03.2007, p. 273-283.

Research output: Contribution to journalArticle

Clewing, JM, Fryssira, H, Goodman, D, Smithson, SF, Sloan, EA, Lou, S, Huang, Y, Choi, K, Lücke, T, Alpay, H, André, JL, Asakura, Y, Biebuyck-Gouge, N, Bogdanovic, R, Bonneau, D, Cancrini, C, Cochat, P, Cockfield, S, Collard, L, Cordeiro, I, Cormier-Daire, V, Cransberg, K, Cutka, K, Deschenes, G, Ehrich, JHH, Fründ, S, Georgaki, H, Guillen-Navarro, E, Hinkelmann, B, Kanariou, M, Kasap, B, Kilic, SS, Lama, G, Lamfers, P, Loirat, C, Majore, S, Milford, D, Morin, D, Özdemir, N, Pontz, BF, Proesmans, W, Psoni, S, Reichenbach, H, Reif, S, Rusu, C, Saraiva, JM, Sakallioglu, O, Schmidt, B, Shoemaker, L, Sigaudy, S, Smith, G, Sotsiou, F, Stajic, N, Stein, A, Stray-Pedersen, A, Taha, D, Taque, S, Tizard, J, Tsimaratos, M, Wong, NACS & Boerkoel, CF 2007, 'Schimke immunoosseous dysplasia: Suggestions of genetic diversity', Human Mutation, vol. 28, no. 3, pp. 273-283. https://doi.org/10.1002/humu.20432
Clewing JM, Fryssira H, Goodman D, Smithson SF, Sloan EA, Lou S et al. Schimke immunoosseous dysplasia: Suggestions of genetic diversity. Human Mutation. 2007 Mar;28(3):273-283. https://doi.org/10.1002/humu.20432
Clewing, J. Marietta ; Fryssira, Helen ; Goodman, David ; Smithson, Sarah F. ; Sloan, Emily A. ; Lou, Shu ; Huang, Yan ; Choi, Kunho ; Lücke, Thomas ; Alpay, Harika ; André, Jean Luc ; Asakura, Yumi ; Biebuyck-Gouge, Nathalie ; Bogdanovic, Radovan ; Bonneau, Dominique ; Cancrini, Caterina ; Cochat, Pierre ; Cockfield, Sandra ; Collard, Laure ; Cordeiro, Isabel ; Cormier-Daire, Valerie ; Cransberg, Karlien ; Cutka, Karel ; Deschenes, Georges ; Ehrich, Jochen H H ; Fründ, Stefan ; Georgaki, Helen ; Guillen-Navarro, Encarna ; Hinkelmann, Barbara ; Kanariou, Maria ; Kasap, Belde ; Kilic, Sara Sebnem ; Lama, Guiliana ; Lamfers, Petra ; Loirat, Chantal ; Majore, Silvia ; Milford, David ; Morin, Denis ; Özdemir, Nihal ; Pontz, Bertram F. ; Proesmans, Willem ; Psoni, Stavroula ; Reichenbach, Herbert ; Reif, Silke ; Rusu, Cristina ; Saraiva, Jorge M. ; Sakallioglu, Onur ; Schmidt, Beate ; Shoemaker, Lawrence ; Sigaudy, Sabine ; Smith, Graham ; Sotsiou, Flora ; Stajic, Natasa ; Stein, Anja ; Stray-Pedersen, Asbjørg ; Taha, Doris ; Taque, Sophie ; Tizard, Jane ; Tsimaratos, Michel ; Wong, Newton A C S ; Boerkoel, Cornelius F. / Schimke immunoosseous dysplasia : Suggestions of genetic diversity. In: Human Mutation. 2007 ; Vol. 28, No. 3. pp. 273-283.
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T2 - Suggestions of genetic diversity

AU - Clewing, J. Marietta

AU - Fryssira, Helen

AU - Goodman, David

AU - Smithson, Sarah F.

AU - Sloan, Emily A.

AU - Lou, Shu

AU - Huang, Yan

AU - Choi, Kunho

AU - Lücke, Thomas

AU - Alpay, Harika

AU - André, Jean Luc

AU - Asakura, Yumi

AU - Biebuyck-Gouge, Nathalie

AU - Bogdanovic, Radovan

AU - Bonneau, Dominique

AU - Cancrini, Caterina

AU - Cochat, Pierre

AU - Cockfield, Sandra

AU - Collard, Laure

AU - Cordeiro, Isabel

AU - Cormier-Daire, Valerie

AU - Cransberg, Karlien

AU - Cutka, Karel

AU - Deschenes, Georges

AU - Ehrich, Jochen H H

AU - Fründ, Stefan

AU - Georgaki, Helen

AU - Guillen-Navarro, Encarna

AU - Hinkelmann, Barbara

AU - Kanariou, Maria

AU - Kasap, Belde

AU - Kilic, Sara Sebnem

AU - Lama, Guiliana

AU - Lamfers, Petra

AU - Loirat, Chantal

AU - Majore, Silvia

AU - Milford, David

AU - Morin, Denis

AU - Özdemir, Nihal

AU - Pontz, Bertram F.

AU - Proesmans, Willem

AU - Psoni, Stavroula

AU - Reichenbach, Herbert

AU - Reif, Silke

AU - Rusu, Cristina

AU - Saraiva, Jorge M.

AU - Sakallioglu, Onur

AU - Schmidt, Beate

AU - Shoemaker, Lawrence

AU - Sigaudy, Sabine

AU - Smith, Graham

AU - Sotsiou, Flora

AU - Stajic, Natasa

AU - Stein, Anja

AU - Stray-Pedersen, Asbjørg

AU - Taha, Doris

AU - Taque, Sophie

AU - Tizard, Jane

AU - Tsimaratos, Michel

AU - Wong, Newton A C S

AU - Boerkoel, Cornelius F.

PY - 2007/3

Y1 - 2007/3

N2 - Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCALl mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.

AB - Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCALl mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.

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KW - Immunodeficiency

KW - Locus heterogeneity

KW - Proteinuria

KW - Skeletal dysplasia

KW - SMARCAL1

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