Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia.
Schimke immuno-osseous dysplasia (SIOD, MIM 242900) is an autosomal-recessive pleiotropic disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. Using genome-wide linkage mapping and a positional candidate approach, we determined that mutations in SMARCAL1 (SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), are responsible for SIOD. Through analysis of data from persons with SIOD in 26 unrelated families, we observed that affected individuals from 13 of 23 families with severe disease had two alleles with nonsense, frameshift or splicing mutations, whereas affected individuals from 3 of 3 families with milder disease had a missense mutation on each allele. These observations indicate that some missense mutations allow retention of partial SMARCAL1 function and thus cause milder disease.
Boerkoel
Cornelius F
CF
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. boerkoel@bcm.tmc.edu
Takashima
Hiroshi
H
John
Joy
J
Yan
Jiong
J
Stankiewicz
Pawel
P
Rosenbarker
Lisa
L
André
Jean-Luc
JL
Bogdanovic
Radovan
R
Burguet
Antoine
A
Cockfield
Sandra
S
Cordeiro
Isabel
I
Fründ
Stefan
S
Illies
Friederike
F
Joseph
Mark
M
Kaitila
Ilkka
I
Lama
Giuliana
G
Loirat
Chantal
C
McLeod
D Ross
DR
Milford
David V
DV
Petty
Elizabeth M
EM
Rodrigo
Francisco
F
Saraiva
Jorge M
JM
Schmidt
Beate
B
Smith
Graham C
GC
Spranger
Jürgen
J
Stein
Anja
A
Thiele
Hannelore
H
Tizard
Jane
J
Weksberg
Rosanna
R
Lupski
James R
JR
Stockton
David W
DW
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D017124:Conserved Sequence; D004247:DNA / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D051437:Renal Insufficiency / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology
D004247:DNA; C412482:SMARCAL1 protein, human; D004265:DNA Helicases