Schimke immunoosseous dysplasia: suggestions of genetic diversity.
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 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.
Clewing
J Marietta
JM
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Fryssira
Helen
H
Goodman
David
D
Smithson
Sarah F
SF
Sloan
Emily A
EA
Lou
Shu
S
Huang
Yan
Y
Choi
Kunho
K
Lücke
Thomas
T
Alpay
Harika
H
André
Jean-Luc
JL
Asakura
Yumi
Y
Biebuyck-Gouge
Nathalie
N
Bogdanovic
Radovan
R
Bonneau
Dominique
D
Cancrini
Caterina
C
Cochat
Pierre
P
Cockfield
Sandra
S
Collard
Laure
L
Cordeiro
Isabel
I
Cormier-Daire
Valerie
V
Cransberg
Karlien
K
Cutka
Karel
K
Deschenes
Georges
G
Ehrich
Jochen H H
JH
Fründ
Stefan
S
Georgaki
Helen
H
Guillen-Navarro
Encarna
E
Hinkelmann
Barbara
B
Kanariou
Maria
M
Kasap
Belde
B
Kilic
Sara Sebnem
SS
Lama
Guiliana
G
Lamfers
Petra
P
Loirat
Chantal
C
Majore
Silvia
S
Milford
David
D
Morin
Denis
D
Ozdemir
Nihal
N
Pontz
Bertram F
BF
Proesmans
Willem
W
Psoni
Stavroula
S
Reichenbach
Herbert
H
Reif
Silke
S
Rusu
Cristina
C
Saraiva
Jorge M
JM
Sakallioglu
Onur
O
Schmidt
Beate
B
Shoemaker
Lawrence
L
Sigaudy
Sabine
S
Smith
Graham
G
Sotsiou
Flora
F
Stajic
Natasa
N
Stein
Anja
A
Stray-Pedersen
Asbjørg
A
Taha
Doris
D
Taque
Sophie
S
Tizard
Jane
J
Tsimaratos
Michel
M
Wong
Newton A C S
NA
Boerkoel
Cornelius F
CF
D000465:Algorithms; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005820:Genetic Testing; D014644:Genetic Variation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010009:Osteochondrodysplasias / Q000235:genetics*; D010641:Phenotype
C412482:SMARCAL1 protein, human; D004265:DNA Helicases