Περίληψη:
Schimke immunoosseous dysplasia (SIOD), which is characterized by
prominent spondyloepiplayseal 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 SMARCAL1 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.
Συγγραφείς:
Clewing, J. Marietta
Fryssira, Helen
Goodman, David and
Smithson, Sarah F.
Sloan, Emily A.
Lou, Shu
Huang, Yan and
Chow, Kunho
Luecke, Thomas
Alpay, Harika
Andre, Jean-Luc and
Asakura, Yumi
Biebuyck-Gouge, Nathalie
Bogdanovic, Radovan and
Bonneau, Dominique
Cancrini, Caterina
Cochat, Pierre and
Cockfield, Sandra
Collard, Laure
Cordeiro, Isabel and
Cormier-Daire, Valerie
Cransberg, Karlien
Cutka, Karel and
Deschenes, Georges
Ehrich, Jochen H. H.
Frund, Stefan and
Georgaki, Helen
Guillen-Navarro, Encarna
Hinkelmann, Barbara and
Kanariou, Maria
Kasap, Belde
Kilic, Sara Sebnem
Lama,
Guiliana
Lamfers, Petra
Loirat, Chantal
Majore, Silvia and
Milford, David
Morin, Denis
Ozdemir, Nihal
Pontz, Bertram F.
and Proesmans, Willem
Psoni, Stavroula
Reichenbach, Herbert and
Reif, Silke
Rusu, Cristina
Saraiva, Jorge M.
Sakallioglu,
Onur
Schmidt, Beate
Shoemaker, Lawrence
Sigaudy, Sabine and
Smith, Graham
Sotsiou, Flora
Stajic, Natasa
Stein, Anja and
Stray-Pedersen, Asbjorg
Taha, Doris
Taque, Sophie
Tizard,
Jane
Tsimaratos, Michel
Wong, Newton A. C. S.
Boerkoel,
Cornelius F.
