Phenotypic and genotypic aspects of Townes-Brock syndrome: case report of patient in southern Brazil with a new SALL1 hotspot region nonsense mutation (original) (raw)
Related papers
Molecular Analysis of SALL1 Mutations in Townes-Brocks Syndrome
The American Journal of Human Genetics, 1999
showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS. To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 additional families with TBS or similar phenotypes for SALL1 mutations. In 9 of these families mutations were identified. None of the mutations has previously been described. Two of these mutations are nonsense mutations, one of which occurred in three unrelated families. Five of the mutations are short deletions. All of the mutations are located 5 of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains. This suggests that only SALL1 mutations that remove the DZF domains result in TBS. We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome. However, phenotypic differences in TBS do not seem to depend on the site of mutation.
Townes-Brocks syndrome and renal dysplasia: a novel mutation in the SALL1 gene
Pediatric Nephrology, 2000
A 14-year-old African-American boy had chronic renal failure and Townes-Brocks syndrome (TBS). There were no affected family members. Features were imperforate anus, rectoperineal fistula, triphalangeal thumb, bifid thumb, rocker bottom feet, bilateral ear tags, satyr ear, sensorineural hearing loss, hypospadias, bilateral renal hypoplasia, and progressive chronic renal failure. Renal and urological anomalies in TBS include renal hypoplasia, renal dysplasia, unilateral renal agenesis, horseshoe kidney, posterior urethral valves, ureterovesical reflux, and meatal stenosis. TBS is caused by a dominantly inherited defect in the gene encoding the SALL1 putative transcription factor, a protein possibly required for urological, renal, limb, ear, brain, and liver development. This patient had a novel mutation in this gene. The extent of renal involvement in patients with TBS should be evaluated for optimum treatment and prediction of prognosis.
A Genotyped Case of Townes–Brocks Syndrome with Absent Pulmonary Valve Syndrome from Turkey
Journal of Pediatric Genetics, 2021
Townes–Brocks syndrome (TBS) is a rare syndrome characterized by triad of anal, ear, and thumb anomalies. Further malformations/anomalies include congenital heart diseases, foot malformations, sensorineural and/or conductive hearing impairment, genitourinary malformations, and anomalies of eye and nervous system. Definitive diagnosis for TBS is confirmed by molecular analysis for mutations in the SALL1 gene. Only one known case of TBS with absent pulmonary valve syndrome (APVS) has been previously described to our knowledge. Here, we report a newborn diagnosed with TBS with APVS and tetralogy of Fallot (TOF) who was found to carry the most common pathogenic SALL1 gene mutation c.826C > T (p.R276X), with its surgical repair and postoperative follow-up. To our knowledge, this is the first genotyped case of TBS from Turkey to date. TBS should be suspected in the presence of ear, anal, and thumb malformations in a neonate. If a patient with TBS and TOF-APVS needs preoperative ventila...
Townes-Brocks syndrome. J Med Genet
Journal of Medical Genetics
Townes-Brocks syndrome (TBS) is an autosomal dominant disorder with multiple malformations and variable expression. Major findings include external ear anomalies, hearing loss, preaxial polydactyly and triphalangeal thumbs, imperforate anus, and renal malformations. Most patients with Townes-Brocks syndrome have normal intelligence, although mental retardation has been noted in a few.
Human Molecular Genetics, 2003
Townes-Brocks syndrome (TBS, OMIM #107480) is an autosomal dominant disorder that causes multiple birth defects including renal, ear, anal and limb malformations. Mutations in SALL1 have been postulated to cause TBS by haploinsufficiency; however, a mouse model carrying a sall1-null allele does not mimic the human syndrome. Since the mutations that cause TBS could express a truncated SALL1 protein containing the domain necessary for transcriptional repression but lacking the complete DNA binding domain, we hypothesized that TBS is due to dominant-negative or gain-of-function activity of a mutant protein. To test this hypothesis, we have created a mutant allele, sall1-DeltaZn2-10, that produces a truncated protein and recapitulates the abnormalities found in human TBS. Heterozygous mice mimic TBS patients by displaying high-frequency sensorineural hearing loss, renal cystic hypoplasia and wrist bone abnormalities. Homozygous sall1-DeltaZn2-10 mutant mice exhibit more severe defects than sall1-null mice including complete renal agenesis, exencephaly, limb and anal deformities. We demonstrate that truncated Sall1 mediates interaction with all Sall family members and could interfere with the normal function of all Sall proteins. These data support a model for the pathogenesis of TBS in which expression of a truncated SALL1 protein causes abnormal development of multiple organs.
European Journal of Medical Genetics, 2009
We report a girl with severe manifestations of Townes-Brocks syndrome (TBS) and a previously unreported serious congenital dysphagia. She is unable to swallow her saliva and consequently chokes frequently with desaturations still existing beyond the second year of life. Involvement of the feet was more extensive than is usually seen in TBS. Mutation analysis of the SALL1 gene, responsible for TBS, resulted in the identification of the de novo hot-spot mutation p.Arg276X. This report adds another rare, but serious manifestation to the multiorgan involvement found in TBS.
Dysmorphology and clinical genetics : official publication of the Center for Birth Defects Information Services, Inc, 1988
Cardiac and renal abnormalities have been reported infrequently in Townes-Brocks syndrome. This paper presents three new patients with this syndrome; previously undescribed cardiac and renal abnormalities consisting of truncus arteriosus, ventricular septal defect, unilateral renal agenesis, and renal dysplasia are presented. The spectrum of findings in this syndrome should include cardiac and renal abnormalities.
Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome
American journal of human genetics, 2018
Townes-Brocks syndrome (TBS) is characterized by a spectrum of malformations in the digits, ears, and kidneys. These anomalies overlap those seen in a growing number of ciliopathies, which are genetic syndromes linked to defects in the formation or function of the primary cilia. TBS is caused by mutations in the gene encoding the transcriptional repressor SALL1 and is associated with the presence of a truncated protein that localizes to the cytoplasm. Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity. By using proximity proteomics, we show that truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97. This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls. Furthermore, TBS-like cells show c...