Connexion

GENATLAS PHENOTYPE

last update : 21-02-2018

Symbol	TBS
Location	16q12.1
Name	Townes-Brocks syndrome
Other name(s)	renal-ear-anal-radial syndrome
Corresponding gene	SALL1
Main clinical features	potential ciliopathy-like disease, with imperforate anus, malformations of the uro genital tract, hypoplastic thumbs, external ear abnormalities and neurosensory deafness end-stage renal disease, polycystic kidneys, foot and genitourinary malformations, and congenital heart disease; although less common, short ribs, intellectual disability, growth retardation, cleft palate, and eye defects
Genetic determination	autosomal dominant
	autosomal recessive
Related entries	. including any cases of Goldenhar syndrome with hemifacial microsomia and radial ray defects
Function/system disorder	congenital malformation
	ear
Type	malformation

Gene product

Name

SALL1 encodes a C2H2 zinc finger transcription factor involved in the regulation of pericentromeric heterochromatin

Mechanism(s)

Gene mutation	Chromosome rearrangement	Effect	Comments

nonsense		truncated protein	dominant-negative, majority of mutations identified, located in 5' to the first double zinc finger domain, resulting in truncated mutations and disturbing localization of heterochromatin, and also down-regulating the synergistic transcriptional enhancement for Wnt signal
various types		haploinsufficiency
	deletion	haploinsufficiency	microdeletions from 3.4kb to 2.6MB resulting in a milder TBS-like phenotype than dominant-negative mutations

Remark(s)

short insertions and deletions, mutation in intron creating an aberrant splice site, mostly truncating mutations

mutations in sporadic Townes-Brocks syndrome are of predominantly paternal origin without obvious paternal age effect

truncated Sall1 protein causes derepression of Sall-responsive target genes, disrupts gene regulation by SALL4 in the heart and may similarly affect

gene regulation in other tissues (Kiefer 2008)

truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97 (PMID: 29395072))

many TBS-causing SALL1 mutations could result in truncated proteins that lack most of the zinc finger pairs likely to mediate chromatin-DNA interactions but retain the N-terminal domain (PMID: 29395072))

Genotype/Phenotype correlations

homozygous SALL1 mutation, c.3160C > T (p.R1054*), associated with multiple congenital anomalies, central nervous system defects, cortical blindness, and absence of psychomotor development (PMID: 23069192))