Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region.
Townes-Brocks syndrome (TBS) is an autosomal dominant malformation syndrome characterized by renal, anal, ear, and thumb anomalies caused by SALL1 mutations. To date, 36 SALL1 mutations have been described in TBS patients. All but three of those, namely p.R276X, p.S372X, and c.1404dupG, have been found only in single families thereby preventing phenotype-genotype correlations. Here we present 20 novel mutations (12 short deletions, five short duplications, three nonsense mutations) in 20 unrelated families. We delineate the phenotypes and report previously unknown ocular manifestations, i.e. congenital cataracts with unilateral microphthalmia. We show that 46 out of the now 56 SALL1 mutations are located between the coding regions for the glutamine-rich domain mediating SALL protein interactions and 65 bp 3' of the coding region for the first double zinc finger domain, narrowing the SALL1 mutational hotspot region to a stretch of 802 bp within exon 2. Of note, only two SALL1 mutations would result in truncated proteins without the glutamine-rich domain, one of which is reported here. The latter is associated with anal, ear, hand, and renal manifestations, indicating that the glutamine-rich domain is not required for typical TBS.
Botzenhart
Elke M
EM
Institut für Humangenetik und Anthropologie, Universität Freiburg, Freiburg, Germany.
Bartalini
Gabriella
G
Blair
Edward
E
Brady
Angela F
AF
Elmslie
Frances
F
Chong
Karen L
KL
Christy
Katie
K
Torres-Martinez
Wilfredo
W
Danesino
Cesare
C
Deardorff
Matthew A
MA
Fryns
Jean-Pierre
JP
Marlin
Sandrine
S
Garcia-Minaur
Sixto
S
Hellenbroich
Yorck
Y
Hay
Beverly N
BN
Penttinen
Maila
M
Shashi
Vandana
V
Terhal
Paulien
P
Van Maldergem
Lionel
L
Whiteford
Margo L
ML
Zackai
Elaine
E
Kohlhase
Jürgen
J
D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*
C104146:SALL1 protein, human; D014157:Transcription Factors