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PubMed1996

Genomic structure of HOXD13 gene: a nine polyalanine duplication causes synpolydactyly in two unrelated families.

Synpolydactyly (SPD) is a limb malformation that shows a characteristic manifestation in both hands and feet. This condition is inherited as an autosomal dominant trait with reduced penetrance. We have recently mapped this locus centromeric to the HOXD8 intragenic marker and suggested the HOXD13 gene as a potential candidate for this condition. The genomic structure of HOXD13 established in this study consists of two exons that encodes a polypeptide of 335 amino acids. The downstream exon at the 3' end of this gene contains the homeodomain sequences that are highly conserved. Sixty-three bp upstream of this exon lies a stretch of intronic CA-repeats that proved to be polymorphic in two different populations. The upstream exon encodes 75% of the entire protein and contains a stretch of 15 normal alanines at its 5' end. Sequence comparison at this position in the homozygous affected individuals identified a total of 24 alanine residues that resulted from a duplication of nine polyalanines. In two unrelated SPD families, this duplication was directly transmitted from the affected parents to their affected, but not unaffected, offspring; in one family its size has remained constant for at least 150 years spanning over seven generations. The presence of this duplication confirmed the status of four normal gene carriers, one incomplete penetrance and two affected individuals who were recombinants for HOXD8 or HOXD13-CA repeat markers. This duplication was not present in 150 chromosomes of unrelated healthy subjects of two different populations.

Adolescent↗
PubMed2000

A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration.

The disks of vertebrate photoreceptors are produced by outgrowths of the plasma membrane. Hence genes that encode retinal proteins targeted to plasma membrane protrusions represent candidates for inherited retinal degenerations. One such candidate is the gene encoding human prominin (mouse)-like 1 (PROML1, previously known as AC133 antigen) which belongs to the prominin family of 5-transmembrane domain proteins. Murine prominin (prom) shows a strong preference for plasma membrane protrusions in a variety of epithelial cells whereas PROML1 is expressed in retinoblastoma cell lines and adult retina. In the present study, molecular genetic analyses of a pedigree segregating for autosomal recessive retinal degeneration indicated that the affected individuals were homozygous for a nucleotide 1878 deletion in PROML1. This alteration is predicted to result in a frameshift at codon 614 with premature termination of translation. Expression of a similar prom deletion mutant in CHO cells indicated that the truncated protein does not reach the cell surface. Immunocytochemistry revealed that prom is concentrated in the plasma membrane evaginations at the base of the outer segments of rod photoreceptors. These findings suggest that loss of prominin causes retinal degeneration, possibly because of impaired generation of the evaginations and/or impaired conversion of the evaginations to disks.

AC133 Antigen↗
PubMed2004

A molecular pathogenesis for transcription factor associated poly-alanine tract expansions.

Poly-alanine (Ala) tract expansions in transcription factors have been shown to be associated with human birth defects such as malformations of the brain, the digits, and other structures. Expansions of a poly-Ala tract from 15 to 22 (+7)-29 (+14) Ala in Hoxd13, for example, result in the limb malformation synpolydactyly in humans and in mice [synpolydactyly homolog (spdh)]. Here, we show that an increase of the Ala repeat above a certain length (22 Ala) is associated with a shift in the localization of Hoxd13 from nuclear to cytoplasmic, where it forms large amorphous aggregates. We observed similar aggregates for expansion mutations in SOX3, RUNX2 and HOXA13, pointing to a common mechanism. Cytoplasmic aggregation of mutant Hoxd13 protein is influenced by the length of the repeat, the level of expression and the efficacy of degradation by the proteasome. Heat shock proteins Hsp70 and Hsp40 co-localize with the aggregates and activation of the chaperone system by geldanamycin leads to a reduction of aggregate formation. Furthermore, recombinant mutant Hoxd13 protein forms aggregates in vitro demonstrating spontaneous misfolding of the protein. We analyzed the mouse mutant spdh, which harbors a +7 Ala expansion in Hoxd13 similar to the human synpolydactyly mutations, as an in vivo model and were able to show a reduction of mutant Hoxd13 and, in contrast to wt Hoxd13, a primarily cytoplasmic localization of the protein. Our results provide evidence that poly-Ala repeat expansions in transcription factors result in misfolding, degradation and cytoplasmic aggregation of the mutant proteins.

Animals↗
PubMed2005

A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2.

Zinc finger-containing Gli proteins mediate responsiveness to Hedgehog (Hh) signaling, with Gli2 acting as the major transcriptional activator in this pathway in mice. The discovery of disease-associated mutations points to a critical role for GLI2 in human Hh signaling as well. Here, we show that human GLI2 contains previously undescribed 5' sequence, extending the amino-terminus an additional 328 amino acids. In vitro, transcriptional activity of full-length GLI2 is up to 30 times lower than that of GLI2DeltaN (previously thought to represent the entire GLI2 protein), revealing the presence of an amino-terminal repressor domain in the full-length protein. GLI2DeltaN also exhibits potent transcriptional activity in vivo: overexpression in mouse skin leads to the formation of Hh-independent epithelial downgrowths resembling basal cell carcinomas, which in humans are associated with constitutive Hh signaling. The discovery of this additional, functionally relevant GLI2 sequence led us to re-examine several pathogenic human GLI2 mutants, now containing the entire amino-terminal domain. On the basis of the functional domains affected by the mutations, mutant GLI2 proteins exhibited either loss-of-function or dominant-negative activity. Moreover, deletion of the amino-terminus abrogated dominant-negative activity of mutant GLI2, revealing that this domain is required for transcriptional repressor activity of pathogenic GLI2. Our results establish the presence of an amino-terminal transcriptional repressor domain that plays a critical role in modulating the function of wild-type GLI2 and is essential for dominant-negative activity of a GLI2 mutant associated with human disease.

Animals↗
PubMedDate not supplied

Unilateral duplication of the great toe with anterolateral tibial bowing.

A syndrome consisting of unilateral duplication of the great toe in association with anterolateral bowing of the tibia is described. Patients with this syndrome have significant pedal difficulties after surgical management, but the tibial bowing spontaneously resolves without treatment. Tibial shortening is noted relative to the fibula. Associated clinodactyly and dysharmonic maturation of carpals and metacarpals are also seen. Current data are most consistent with a developmental rather than a genetic etiology.

Abnormalities, Multiple↗
PubMed1997

Exclusion of the p75 neurotrophin receptor gene as a candidate gene for Meckel syndrome.

Nerve growth factor receptor p75 (NGFR) gene was investigated as a potential candidate gene in Meckel syndrome (MKS) because of its important role in embryonic development, chromosomal localization adjacent to the MKS locus and Meckel syndrome-resembling findings in knock-out mice phenotype. The sequence analysis of the coding region of the gene revealed one polymorphism but no potential disease mutation. Physical mapping of the critical chromosomal region finally showed that the NGFR gene lies outside the MKS locus.

Abnormalities, Multiple↗
PubMed2002

Penile agenesis and clavicular anomaly in a child with an oral facial digital syndrome.

We report a male patient with the clinical characteristics of an OFDS (oral facial digital syndrome). He also has penile agenesis, clavicular flattening and cerebellar anomalies. This patient was classified as a severe form of OFD type II-Mohr syndrome but the possibility of this being OFDS VI-Varadi syndrome or a new form of OFDS cannot completely be excluded.

Abnormalities, Multiple↗
PubMed2003

Fuhrmann syndrome: two Brazilian cases.

We describe two unrelated boys with bilateral fibula aplasia, poly- and oligodactyly, and bowed tibiae in two non-consanguineous Brazilian families. These cases are similar to those reported by Fuhrman et al. [(1980). Skeletal Dysplasias. New York: Alan R. Liss Inc. pp. 519-524].

Fibula↗
PubMed2006

Genitourinary malformations as a feature of the Pallister-Hall syndrome.

Pallister-Hall and McKusick-Kaufman syndromes are developmental disorders with well defined phenotypes, distinct loci and different patterns of inheritance. The clinical features can overlap and may cause diagnostic difficulty, particularly if complex genitourinary malformations are present. A case is presented with features of both syndromes but in which a GLI3 mutation has been identified. A literature review of similar cases is presented and it is proposed that these cases probably represent the Pallister-Hall syndrome. A detailed abdominal and perineal examination should be considered in all female patients with the Pallister-Hall syndrome, looking for associated genitourinary anomalies. Conversely, all girls with features suggestive of McKusick-Kaufman syndrome require neuroimaging to look for features of the Pallister-Hall syndrome. The correct diagnosis is important so that the patient and the family may receive appropriate management. It also allows provision for an accurate recurrence risk.

Child, Preschool↗
PubMed2000

Morphologic and radiographic characterization of fibular dimelia.

Fibular dimelia accompanied by complete tibial agenesis is a rare developmental anomaly that has been reported in the anatomic and clinical literature as both a dimelia and a diplopodia. Previous reports have offered variable descriptions of structural aberration and possible modes of altered embryologic development. We present a clinical and radiographic history of the progressive development of this anomaly, and a detailed postsurgical dissection and histopathologic examination. The specific mirroring of the separate components in this case has not been previously reported, and suggests that a reestablishment of limb polarity may have occurred during embryogenesis. Our detailed morphologic investigation strongly suggests a central role for the mesenchymal precursor from which chondro-osseous morphology subsequently emerges, and the relevance to establishing muscular attachments.

Amputation, Surgical↗
PubMed2000

Duplication of the leg--renal agenesis: congenital malformation syndrome.

A case is given of a male born with a duplication of the left leg and ipsilateral kidney agenesis. Although the etiology is unknown, we believe this association represents a congenital malformation syndrome. It is a polytopic developmental field defect. The growth factor IGF-I produced by the intermediary mesoderm or mesonephros (embryonary kidney) could be implicated in the induction limb development and the application of FGF-8 protein to the flank of young chick embryos inducing the development of additional limbs. It is possible that one or more of the growth factors produced by the mesonephros take some cells of the intermediary mesoderm out of their renal way to form a supernumerary limb.

Fibroblast Growth Factor 8↗