Pathological missense mutations of neural cell adhesion molecule L1 affect homophilic and heterophilic binding activities.
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Mutations in the gene for neural cell adhesion molecule L1 (L1CAM) result in a debilitating X-linked congenital disorder of brain development. At the neuronal cell surface L1 may interact with a variety of different molecules including itself and two other CAMs of the immunoglobulin superfamily, axonin-1 and F11. However, whether all of these interactions are relevant to normal or abnormal development has not been determined. Over one-third of patient mutations are single amino acid changes distributed across 10 extracellular L1 domains. We have studied the effects of 12 missense mutations on binding to L1, axonin-1 and F11 and shown for the first time that whereas many mutations affect all three interactions, others affect homophilic or heterophilic binding alone. Patient pathology is therefore due to different types of L1 malfunction. The nature and functional consequence of mutation is also reflected in the severity of the resultant phenotype with structural mutations likely to affect more than one binding activity and result in early mortality. Moreover, the data indicate that several extracellular domains of L1 are required for homophilic and heterophilic interactions. (+info)
A genomic rearrangement resulting in a tandem duplication is associated with split hand-split foot malformation 3 (SHFM3) at 10q24.
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Split hand-split foot malformation (SHFM) is characterized by hypoplasia/aplasia of the central digits with fusion of the remaining digits. SHFM is usually an autosomal dominant condition and at least five loci have been identified in humans. Mutation analysis of the DACTYLIN gene, suspected to be responsible for SHFM3 in chromosome 10q24, was conducted in seven SHFM patients. We screened the coding region of DACTYLIN by single-strand conformation polymorphism and sequencing, and found no point mutations. However, Southern, pulsed field gel electrophoresis and dosage analyses demonstrated a complex rearrangement associated with a approximately 0.5 Mb tandem duplication in all the patients. The distal and proximal breakpoints were within an 80 and 130 kb region, respectively. This duplicated region contained a disrupted extra copy of the DACTYLIN gene and the entire LBX1 and beta-TRCP genes, known to be involved in limb development. The possible role of these genes in the SHFM3 phenotype is discussed. (+info)
THE DE LANGE SYNDROME: REPORT OF THREE CASES.
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Three cases of de Lange's syndrome are described. This condition is characterized by generally severe mental retardation, reduced stature, mild microcephaly, hypertrichosis, various anomalies of hands and feet, and a peculiar facies. The most outstanding features of the latter are the low forehead, profuse, generally confluent eyebrows, abundant long eyelashes, eyes that frequently slant downwards and outwards in antimongoloid fashion, pug nose with prominent anteverted nostrils, increased distance between nose and vermilion border of upper lip, slight reduction in size of chin, and often abnormally low-placed ears. The etiology of de Lange's syndrome is at present unknown. (+info)
Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems.
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BACKGROUND: Heterozygous mutations in the COL1A1 or COL1A2 gene encoding the alpha1 and alpha2 chain of type I collagen generally cause either osteogenesis imperfecta or the arthrochalasis form of Ehlers-Danlos syndrome (EDS). Homozygous or compound heterozygous COL1A2 mutations resulting in complete deficiency of the proalpha2(I) collagen chains are extremely rare and have been reported in only a few patients, albeit with variable phenotypic outcome. METHODS: The clinical features of the proband, a 6 year old boy, were recorded. Analysis of proalpha and alpha-collagen chains was performed by SDS-polyacrylamide gel electrophoresis using the Laemmli buffer system. Single stranded conformation polymorphism analysis of the proband's DNA was also carried out. RESULTS: In this report we show that complete lack of proalpha2(I) collagen chains can present as a phenotype reminiscent of mild hypermobility EDS during childhood. CONCLUSIONS: Biochemical analysis of collagens extracted from skin fibroblasts is a powerful tool to detect the subset of patients with complete absence of proalpha2(I) collagen chains, and in these patients, careful cardiac follow up with ultrasonography is highly recommended because of the risk for cardiac valvular problems in adulthood. (+info)
EEC syndrome sans clefting: variable clinical presentations in a family.
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Ectrodactyly, ectodermal dysplasia and cleft palate/lip syndrome (EEC) is a rare autosomal dominant syndrome with varied presentation and is actually a multiple congenital anomaly syndrome leading to intra- and interfamilial differences in severity because of its variable expression and reduced penetrance. The cardinal features include ectrodactyly, sparse, wiry, hypopigmented hair, peg-shaped teeth with defective enamel and cleft palate/lip. A family comprising father, daughter and son presented to us with split hand-split foot deformity (ectrodactyly), epiphora, hair changes and deafness with variable involvement in each family member. (+info)
Systemic sclerosis.
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Systemic sclerosis (scleroderma) is a rare generalized disorder of connective tissue origin. This condition is predominantly a clinical diagnosis, based on the clinical signs and symptoms. Here is a case report of 26-year-old female patient with the classical features of this disease. This case is reported for its rarity and variable expressivity. This article also reviews the literature of this uncommon condition. (+info)
Loss of dermatan-4-sulfotransferase 1 function results in adducted thumb-clubfoot syndrome.
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Another case of microcephaly, facial clefting, and preaxial polydactyly.
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We describe a nine month old boy with failure to thrive, developmental delay, bilateral cleft lip and palate, and left preaxial polydactyly. The features are similar to those in a child described by Howard and Young and may be the second case of a previously unknown syndrome. (+info)