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Biomedical subjects

Alan Shanske

Publications and source records attributed to Alan Shanske.

9 recordsLinked to original sources
PubMed2006

Dissection of Tbx1 and Fgf interactions in mouse models of 22q11DS suggests functional redundancy.

The 22q11 deletion syndrome (22q11DS) is characterized by abnormal development of the pharyngeal apparatus. Mouse genetic studies have identified Tbx1 as a key gene in the etiology of the syndrome, in part, via interaction with the fibroblast growth factor (Fgf) genes. Three murine Fgfs, Fgf3, Fgf8 and Fgf10 are coexpressed in different combinations with Tbx1. They are all strongly downregulated in Tbx1-/- embryos, implicating epistatic interactions. Supporting this, Tbx1 and Fgf8 have been shown to genetically interact in the development of the fourth pharyngeal arch artery (PAA) and Fgf10 was identified to be a direct downstream target of Tbx1. To dissect the epistatic relationships of these genes during embryonic development and the molecular pathogenesis of the Tbx1 mutant phenotype, we generated Fgf10+/-;Tbx1+/- and Fgf3-/-;Tbx1+/- mice. Despite strong hypotheses that Fgf10 is the key gene downstream of Tbx1 in the development of the anterior heart field, we do not find evidence for genetic interaction between Tbx1 and Fgf10. Also, the Fgf3-/-;Tbx1+/- mutant mice do not show an additive phenotype. Furthermore, more severe defects do not occur in Fgf8+/-;Tbx1+/- mutants by crossing in the Fgf3 null allele. There is a possible additive effect only in PAA remodeling in the Fgf10+/-;Tbx1+/-;Fgf8+/- embryos. Our findings underscore the importance of potential functional redundancy with additional Fgfs in the development of the pharyngeal apparatus and cardiovascular system via Tbx1. This redundancy should be considered when looking at individual FGF genes as modifiers of 22q11DS.

Animals↗
PubMed2006

T-genes and limb bud development.

The T-box family of transcriptional factors is ancient and highly conserved among most species of animals. Haploinsufficiency of multiple T-box proteins results in severe human congenital malformation syndromes, involving craniofacial, cardiovascular, and skeletal structures. These genes have major roles in embryogenesis, including the development of the limbs. Formation of the limbs begins with a limb bud and its morphogenesis requires complex epithelial-mesenchymal interactions. Recent studies have shown that T, Tbx2, Tbx3, Tbx4, Tbx5, Tbx15, and Tbx18 are all expressed in the limb buds, and many have developmental functions. The study of these genes is clinically relevant as mutations in several of them cause human congenital malformation syndromes. Furthermore, understanding the function and biology of these genes is important in understanding normal embryogenesis.

Gene Expression Regulation, Developmental↗
PubMed2005

Clinical and genetic features in two families with MELAS and the T3271C mutation in mitochondrial DNA.

The majority of patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) have the A3243G point mutation. The much rarer T3271C mutation has been reported predominantly in Japanese subjects. Our objective was to better define the clinical phenotype and mutation load in patients with MELAS and the T3271C mutation in mitochondrial DNA. We present clinical and molecular genetic data in two pedigrees with the T3271C mutation. The age at onset was 8 years in one proband and 14 years in the other. Both patients had migrainelike headache, seizures, and strokelike episodes. Mutation loads were quantified in multiple tissues from the patients and from family members by polymerase chain reaction-restriction fragment length polymorphism analysis. The symptoms in both probands were typical of MELAS, and, contrary to previous reports, onset was early. Hearing loss was less common than in typical MELAS, and ragged red fibers were absent. The proportion of mutant genomes was consistently and markedly greater in DNA from urinary sediment than from blood. In the mother of one proband, mutant genomes were detected only in DNA from hair follicles and cheek mucosa The phenotype of patients with the T3271C mutation might not be as distinct as that of the A3243G mutation, as previously described. Our data also suggest that urine is a better source of DNA than blood for diagnosis and that multiple tissues should be studied in maternal relatives, especially when the mutation cannot be detected in blood.

Adolescent↗
PubMed2003

Frequent translocations occur between low copy repeats on chromosome 22q11.2 (LCR22s) and telomeric bands of partner chromosomes.

The chromosome 22q11.2 region is susceptible to rearrangements, mediated by low copy repeats (LCR22s). Deletions and duplications are mediated by homologous recombination events between LCR22s. The recurrent balanced constitutional translocation t(11;22)(q23;q11) breakpoint occurs in an LCR22 and is mediated by double strand breaks in AT-rich palindromes on both chromosomes 11 and 22. Recently, two cases of a t(17;22)(q11;q11) were reported, mediated by a similar mechanism (21). Except for these constitutional translocations, the molecular basis for non-recurrent, reciprocal 22q11.2 translocations is not known. To determine whether there are specific mechanisms that could mediate translocations, we analyzed cell lines derived from 14 different individuals by genotyping and FISH mapping. Somatic cell hybrid analysis was carried out for four cell lines. In five cell lines, the translocation breakpoints occurred in the same LCR22 as for the t(11;22) translocation, suggesting that similar molecular mechanisms are responsible. An additional three occurred in other LCR22s, and six were in non-LCR22 regions, mostly in the proximal half of the 22q11.2 region. The translocation breakpoints on the partner chromosomes were all located in the telomeric bands, proximal to the most telomeric unique sequence probe, in eight cell lines and distal to those loci in six. Therefore, several of the breakpoints were found to occur in the vicinity of highly dynamic regions of the genome, 22q11.2 and telomeric bands. We hypothesize that these regions are more susceptible to breakage and repair, resulting in translocations.

Base Sequence↗
PubMed2002

Mental retardation and abnormal skeletal development (Dyggve-Melchior-Clausen dysplasia) due to mutations in a novel, evolutionarily conserved gene.

Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC) are similar, rare autosomal recessive osteochondrodysplasias. The radiographic features and cartilage histology in DMC and SMC are identical. However, patients with DMC exhibit significant developmental delay and mental retardation, the major features that distinguish the two conditions. Linkage studies localized the SMC and DMC disease genes to chromosome 18q12-21.1, providing evidence suggesting that they are allelic disorders. Sequence analysis of the coding exons of the FLJ90130 gene, a highly evolutionarily conserved gene within the recombination interval defined in the linkage study, identified mutations in SMC and DMC patients. The affected individuals in two consanguinous DMC families were homozygous for a stop codon mutation and a frameshift mutation, respectively, demonstrating that DMC represents the FLJ90130-null phenotype. The data confirm the hypothesis that SMC and DMC are allelic disorders and identify a gene necessary for normal skeletal development and brain function.

Amino Acid Sequence↗
PubMed2002

Evidence that Smith-McCort dysplasia and Dyggve-Melchior-Clausen dysplasia are allelic disorders that result from mutations in a gene on chromosome 18q12.

Smith-McCort dysplasia is a rare autosomal recessive osteochondrodysplasia characterized by short limbs and a short trunk with a barrel-shaped chest. The radiographic phenotype includes platyspondyly, generalized abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest. We performed a genomewide scan in a consanguineous family from Guam and found evidence of linkage to loci on chromosome 18q12. Analysis of a second, smaller family was also consistent with linkage to this region, producing a maximum combined two-point LOD score of 3.04 at a recombination fraction of 0 for the marker at locus D18S450. A 10.7-cM region containing the disease gene was defined by recombination events in two affected individuals in the larger family. Furthermore, all affected children in the larger family were homozygous for a subset of marker loci within this region, defining a 1.5-cM interval likely to contain the defective gene. Analysis of three small, unrelated families with Dyggve-Melchior-Clausen syndrome, a radiographically identical disorder with the additional clinical finding of mental retardation, provided evidence of linkage to the same region, a result consistent with the hypothesis that the two disorders are allelic.

Alleles↗
PubMed2002

A recurring FBN1 gene mutation in neonatal Marfan syndrome.

BACKGROUND: Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in the fibrillin 1 gene (FBN1). FBN1 mutations have been associated with a broad spectrum of phenotypes. Neonatal Marfan syndrome has unique clinical manifestations and mutations. OBJECTIVE: To determine if there is a discernible genotypic-phenotypic correlation associated with the unique mutation in neonatal Marfan syndrome. STUDY DESIGN: A newborn exhibited many typical characteristics of neonatal Marfan syndrome, including arachnodactyly; contractures of both elbows, knees, and ankles; small-joint laxity; dilated cardiomyopathy; valvular dysplasia and insufficiency; congestive heart failure; and pulmonary emphysema. Three atypical features were also discovered: a right diaphragmatic hernia, a myocardial mass, and left main-stem bronchomalacia. She died at 3(1/2) months of age. Total RNA was extracted from skin fibroblasts and amplified by means of reverse transcriptase polymerase chain reaction amplification with FBN1-specific primers. The complementary DNA fragments were sequenced. RESULTS: A single T-to-C transition at nucleotide 3276 (T3276C) was identified and confirmed at the DNA level by sequencing of genomic DNA. This results in a substitution of threonine for isoleucine. CONCLUSIONS: Neonatal Marfan syndrome is a unique clinical entity with recurring mutation hot spots in exons 24 to 27 and 31 to 32 of the FBN1 gene. Some clinical features in this case report are unusual for neonatal Marfan syndrome. This is the third report of this T3276C mutation in the FBN1 gene with unusual clinical manifestations. We conclude that there is a genotypic-phenotypic correlation associated with this mutation.

Abnormalities, Multiple↗
PubMedDate not supplied

Craniofacial characteristics evidenced in Bartsocas-Papas syndrome from birth to five years. Case report.

Bartsocas-Papas Syndrome (BPS) is a rare congenital disorder, first described in 1972. It is usually characterized by neonatal or intrauterine death, and, as such, only 26 cases have been reported. Physical manifestations such as antecubital and popliteal pterygia (webbing), syndactyly of fingers, toes and talipes are frequently reported. However, oral, facial, cranial and dental anomalies are often overlooked. This case focuses on the latter anomalies and the effect they have on the facial growth of a 5-year-old patient.

Abnormalities, Multiple↗