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Biomedical subjects

D G Phillips

Publications and source records attributed to D G Phillips.

13 recordsLinked to original sources
PubMed1988

Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man.

L1 sequences are a human-specific family of long, interspersed, repetitive elements, present as approximately 10(5) copies dispersed throughout the genome. The full-length L1 sequence is 6.1 kilobases, but the majority of L1 elements are truncated at the 5' end, resulting in a fivefold higher copy number of 3' sequences. The nucleotide sequence of L1 elements includes an A-rich 3' end and two long open reading frames (orf-1 and orf-2), the second of which encodes a potential polypeptide having sequence homology with the reverse transcriptases. This structure suggests that L1 elements represent a class of non-viral retrotransposons. A number of L1 complementary DNAs, including a nearly full-length element, have been isolated from an undifferentiated teratocarcinoma cell line. We now report insertions of L1 elements into exon 14 of the factor VIII gene in two of 240 unrelated patients with haemophilia A. Both of these insertions (3.8 and 2.3 kilobases respectively) contain 3' portions of the L1 sequence, including the poly (A) tract, and create target site duplications of at least 12 and 13 nucleotides of the factor VIII gene. In addition, their 3'-trailer sequences following orf-2 are nearly identical to the consensus sequence of L1 cDNAs (ref. 6). These results indicate that certain L1 sequences in man can be dispersed, presumably by an RNA intermediate, and cause disease by insertional mutation.

Base Sequence↗
PubMed1988

Restriction endonuclease mapping of six novel deletions of the factor VIII gene in hemophilia A.

Hemophilia A is an X-linked disease of blood coagulation caused by deficiency of factor VIII. Using cloned cDNA, genomic and synthetic oligonucleotide factor VIII probes, we have identified six novel partial gene deletions in patients with severe hemophilia A. We have previously reported six other deletions of the factor VIII gene. The number of gross molecular defects (deletions, insertions) in the factor VIII gene in our series of 240 patients is 17 (3 insertions and 2 complicated deletions will be described elsewhere). No association was observed between the size or location of the deletions and the presence of inhibitors to factor VIII. No deletion breakpoint "hotspots" have been identified by restriction analysis. The parental origin of several of the deletions was determined.

Adolescent↗
PubMed1987

Three additional DNA polymorphisms in the met gene and D7S8 locus: use in prenatal diagnosis of cystic fibrosis.

We have used cloned DNA sequences from the 5' end of the met locus and the D7S8 locus to locate new restriction fragment length polymorphisms. TaqI and MspI polymorphisms with frequencies of 0.34/0.66 and 0.10/0.90, respectively, for met and a PvuII polymorphism (0.15/0.85) at D7S8 are described. We used these new markers to analyze our reference panel of cystic fibrosis pedigrees and found that they provided additional information in several families. No evidence for recombination was observed between the 5' end of met and previously described met markers. We present examples of the use of the met markers in the clinical diagnosis of cystic fibrosis and summarize our analysis of 29 clinical cases including eight prenatal diagnoses. We conclude that DNA-based prediction of cystic fibrosis is an effective clinical diagnostic procedure.

Alleles↗
PubMed1987

Characterization of five partial deletions of the factor VIII gene.

Hemophilia A is an X-linked disorder of coagulation caused by a deficiency of factor VIII. By using cloned DNA probes, we have characterized the following five different partial deletions of the factor VIII gene from a panel of 83 patients with hemophilia A: (i) a 7-kilobase (kb) deletion that eliminates exon 6; (ii) a 2.5-kb deletion that eliminates 5' sequences of exon 14; (iii) a deletion of at least 7 kb that eliminates exons 24 and 25; (iv) a deletion of at least 16 kb that eliminates exons 23-25; and (v) a 5.5-kb deletion that eliminates exon 22. The first four deletions are associated with severe hemophilia A. By contrast, the last deletion is associated with moderate disease, possibly because of in-frame splicing from moderate disease, possibly because of in-frame splicing from adjacent exons. None of those patients with partial gene deletions had circulating inhibitors to factor VIII. One deletion occurred de novo in a germ cell of the maternal grandmother, while a second deletion occurred in a germ cell of the maternal grandfather. These observations demonstrate that de novo deletions of X-linked genes can occur in either male or female gametes.

Chromosome Deletion↗
PubMed1981

Calcium ions, morphine tolerance and noradrenergic transmission in the mouse vas deferens.

The response of the isolated vas deferens of the mouse to electrical stimulation is inhibited by morphine and levorphanol via an opiate receptor, the inhibition decreasing with increasing stimulation frequency (0.2-16 Hz). Tolerance to the locomotor stimulant effect of morphine was induced over 48 h using a slow release preparation. Vasa from mice similarly treated with the slow release preparation showed a shift to the right of the morphine and levorphanol twitch inhibition curves. The reduction in the fractional release of [3H]noradrenaline by morphine and levorphanol was less in vasa from morphine-pretreated mice. Altering the Krebs solution by reducing the Ca2+ or Na+ or adding Mg2+ increased the effect of opiate agonists in vasa from naive and morphine-tolerant mice. Therefore, tolerance to morphine has not changed the ability of these ions to modulate opiate responses.

Animals↗
PubMed1976

The shoulder girdle disc.

Weakness and wasting of shoulder girdle muscles occurred in 40 cases of cervical spondylosis at the level C 3/4 intervertebral space with spinal cord, and lower with nerve root compression. Often there was no sensory loss. Prompt recovery followed Cloward's operation in more than half the cases. The pathogenesis and the need for early diagnosis and radical treatment of the condition are considered.

Cervical Vertebrae↗
PubMed1975

Upper limb involvement in cervical spondylosis.

Analysis of 200 cases reveals that the two neurological syndromes, brachial neuritis and myelopathy, associated with cervical spondylosis are distinct with relatively little overlap. While upper limb motor and sensory loss are doubtless due to nerve root compression in cases of "pure' brachial neuritis, they are more likely to be due to cord damage in cases with myelopathy (with spastic paraparesis of lower limbs). In either group of cases, neurological features in the upper limbs are not very helpful in localizing the level of significant intervertebral disc pathology. Contrast radiology (myelography and possibly discography) is a reliable guide judging by the excellent results obtained by anterior route (Cloward's) operation at specific disc levels in a series of cases with longstanding complaints unrelieved by conservative treatment. Pathological data provide a rational basis for interpretation of clinical observations and for surgical treatment.

Adult↗
PubMed1973

Surgical treatment of myelopathy with cervical spondylosis.

The results of treatment over a period of 10 years of 102 cases of cervical spondylosis with myelopathy are presented, with a complete follow-up in all cases to two years after the end of that period. Results similar to those previously recorded were obtained with treatment by a light Minerva plaster collar, or laminectomy, but the best results, 73% sustained improvement, were obtained in 65 cases treated from an anterior approach, by Cloward's operation. Of 48 patients showing sustained improvement, 38 returned to, and remained at work. Cloward's operation was first undertaken at the beginning of the 10 year period, and was increasingly adopted as a primary procedure. It became evident that benefit from any treatment in cases with symptoms of long duration was likely to be limited, and the best results were in cases with less than a year's history who had Cloward's operation (86% sustained improvement). The necessity for careful clinical and radiological diagnosis, and operative technique, is emphasized, also the desirability of careful scrutiny of assessments in series of this disorder.

Aged↗
PubMedDate not supplied

Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots.

Haemophilia A is a common disorder of blood coagulation caused by a deficiency of factor VIII. It is inherited as an X-linked recessive trait, and one-third of all cases are thought to result from de novo mutations. The clinical severity of haemophilia A varies markedly among different families and a subset of the patients with severe disease develop antibodies against factor VIII, called inhibitors. Because of this heterogeneity, it is likely that many different molecular lesions result in haemophilia A. Indeed, of the nine mutations described to date, all appear to be unique changes. However in this study of 83 patients with haemophilia A we have identified two different point mutations, one in exon 18 and one in exon 22, that have recurred independently in unrelated families. Each mutation produces a nonsense codon by a change of CG to TG, and each occurred de novo on the X-chromosome donated by the maternal grandfather. These observations strongly support the view that CpG dinucleotides are mutation hotspots.

Base Composition↗