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The spectrum of mutations in TBX3: Genotype/Phenotype relationship in ulnar-mammary syndrome.

ABSTRACT: Ulnar-mammary syndrome (UMS) is a pleiotropic disorder affecting limb, apocrine-gland, tooth, hair, and genital development. Mutations that disrupt the DNA-binding domain of the T-box gene, TBX3, have been demonstrated to cause UMS. However, the 3' terminus of the open reading frame (ORF) of TBX3 was not identified, and mutations were detected in only two families with UMS. Furthermore, no substantial homology outside the T-box was found among TBX3 and its orthologues. The subsequent cloning of new TBX3 cDNAs allowed us to complete the characterization of TBX3 and to identify alternatively transcribed TBX3 transcripts, including one that interrupts the T-box. The complete ORF of TBX3 is predicted to encode a 723-residue protein, of which 255 amino acids are encoded by newly identified exons. Comparison of other T-box genes to TBX3 indicates regions of substantial homology outside the DNA-binding domain. Novel mutations have been found in all of eight newly reported families with UMS, including five mutations downstream of the region encoding the T-box. This suggests that a domain(s) outside the T-box is highly conserved and important for the function of TBX3. We found no obvious phenotypic differences between those who have missense mutations and those who have deletions or frameshifts.

SUBMITTER: Bamshad M

PROVIDER: S-EPMC1377898 | biostudies-other | 1999 Jun

REPOSITORIES: biostudies-other

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The spectrum of mutations in TBX3: Genotype/Phenotype relationship in ulnar-mammary syndrome.

Bamshad M M Le T T Watkins W S WS Dixon M E ME Kramer B E BE Roeder A D AD Carey J C JC Root S S Schinzel A A Van Maldergem L L Gardner R J RJ Lin R C RC Seidman C E CE Seidman J G JG Wallerstein R R Moran E E Sutphen R R Campbell C E CE Jorde L B LB

American journal of human genetics 19990601 6

Ulnar-mammary syndrome (UMS) is a pleiotropic disorder affecting limb, apocrine-gland, tooth, hair, and genital development. Mutations that disrupt the DNA-binding domain of the T-box gene, TBX3, have been demonstrated to cause UMS. However, the 3' terminus of the open reading frame (ORF) of TBX3 was not identified, and mutations were detected in only two families with UMS. Furthermore, no substantial homology outside the T-box was found among TBX3 and its orthologues. The subsequent cloning of ...[more]

PMID: 10330342

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Project description:Purpose:To describe the mutation spectrum of SPATA7 and associated ocular phenotypes. Methods:As part of a continuing examination of the genetic basis of inherited ophthalmic diseases, sequencing variations in SPATA7 were identified in sequencing data from 5,090 probands. Mutations in SPATA7 were identified in 12 Chinese patients from ten families. Family history and clinical data were examined in detail in these patients. To evaluate possible gene-specific fundus changes, the results were combined with data from 66 patients from 50 families previously reported in the literature. Results:Seven homozygous or compound heterozygous mutations, including two novel mutations (c.367C>T, p.Q123* and c.1083-2A>G) and five known mutations in SPATA7, were identified in ten families, including six families with Leber congenital amaurosis (LCA), three families with juvenile retinitis pigmentosa, and one family with early-onset high myopia. These families accounted for approximately 2.2% (6/269) of LCA and 0.4% (10/2,252) of inherited retinal dystrophies in this case series. A combined analysis of data from the present study and data from 60 families reported in the literature showed that 93.3% (112/120) of mutant alleles were truncation mutations, whereas only about 5.0% were missense mutations, and 1.7% were non-frameshift indels. Common SPATA7-associated fundus changes, including narrow arterioles, a relatively well-preserved macular region, and widespread RPE atrophy resulting in diffuse mottled hypopigmentation in the midperipheral retina, were identified in this cohort and in patients in the literature. Missense mutations were not associated with specific phenotypic features or severity. Conclusions:Narrow arterioles, a relatively well-preserved macular region, and widespread RPE atrophy resulting in diffuse mottling hypopigmentation in the midperipheral retina may be considered early and common fundus changes specific to SPATA7-associated retinopathy. The fact that similar mutations result in varied phenotypes points to the existence of other potential modifiers of the disease. Uncovering the identity of these modifiers might aid the development of novel treatments.

Dataset Information

The spectrum of mutations in TBX3: Genotype/Phenotype relationship in ulnar-mammary syndrome.

Publications

The spectrum of mutations in TBX3: Genotype/Phenotype relationship in ulnar-mammary syndrome.

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