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M A Cleary

Publications and source records attributed to M A Cleary.

16 recordsLinked to original sources
PubMed1996

The Oct-1 POU-specific domain can stimulate small nuclear RNA gene transcription by stabilizing the basal transcription complex SNAPc.

The RNA polymerase II and III human small nuclear RNA promoters have a common basal element, the proximal sequence element, which binds the TATA box-binding protein-containing complex SNAPc. They also contain an enhancer characterized by a highly conserved octamer sequence, which constitutes a binding site for the broadly expressed POU domain transcription factor Oct-1. The POU domain is a bipartite DNA-binding domain consisting of a POU-homeo (POUH) domain and a POU-specific (POUs) domain joined by a flexible linker. Here, we show that the Oct-1 POU domain but not the related Pit-1 POU domain can facilitate the binding of SNAPc to the proximal sequence element, and activate transcription. The effect is probably mediated by protein-protein contacts, and 1 of 30 amino acid differences between the Oct-1 and Pit-1 POUs domains is the key determinant for the differential interaction with SNAPc and the ability to activate transcription. These results show that a function that is the hallmark of activation domains, namely, recruitment of a basal transcription complex resulting in activation of transcription, can be performed by a DNA-binding domain. In this case, subtle changes between activator DNA-binding domains, as subtle as a single amino acid difference, can profoundly affect interaction with the basal transcription machinery.

Amino Acid Sequence↗
PubMed1996

Histidinaemia: a benign metabolic disorder.

Histidinaemia is a relatively common inherited metabolic disorder with an incidence similar to phenylketonuria. This paper reports the long term outcome of patients diagnosed by newborn screening in the north west of England. Between 1966 and 1990, 108 infants were diagnosed as having histidinaemia by a regional neonatal screening programme (incidence 1:11,083). A further five children were detected following diagnosis in a sibling. Of the 113, nine were lost to follow up. Infants diagnosed before 1981 (n = 47) were placed on a low histidine diet (225 mg/kg/d) for an average period of 21 months (SD 4.5). All patients were reviewed regularly, Griffiths developmental quotients (DQ) were assessed at 2 and 4 years, and WISC-R intelligence quotients (IQ) at 8, 12, and 18 years. IQ data were converted to standard deviation scores (IQ SDS) to account for increasing IQ norms with time. Neither DQ nor IQ correlated with plasma histidine at diagnosis or with the mean plasma histidine throughout life. Growth was normal in all patients. There was no apparent benefit from a low histidine diet in early childhood. In contrast to other studies, there was no excess of clinical symptoms. On the basis of these findings, histidinaemia is a benign metabolic disorder that does not require treatment.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

Magnetic resonance imaging in phenylketonuria: reversal of cerebral white matter change.

OBJECTIVES: To investigate the extent to which the abnormalities in cerebral white matter in adolescents and adults with phenylketonuria (PKU) are reversible. METHOD: Magnetic resonance imaging (MRI) of the brain was repeated in 41 patients with PKU (age range, 14 to 49 years) after an interval (median, 9 months; range, 3 to 12 months) of dietary intervention. Scans were scored according to the extent of the white matter involvement. After an initial MRI, five patients returned to a strict low-phenylalanine diet with amino acid supplement; 21 patients started a low-protein diet (1 gm/kg) with amino acids supplement; and 15 patients made no dietary alteration. RESULTS: Scans improved in all five patients who returned to a strict low-phenylalanine diet, in 5 of the 21 patients on the low-protein diet plus amino acid supplement, and in 4 of the 15 patients who made no dietary change. There was a significant association between change in the MRI findings and in the blood phenylalanine concentration (Pearson correlation: r = 0.55; p < 0.0002) and between change in the MRI and in the phenylalanine level at the time of the second scan (r = 0.58; p < 0.0001). Improvement was seen primarily in those in whom phenylalanine levels were reduced to less than 900 mumol/L. There was no obvious change in MRI score after 3 weeks of strict phenylalanine restriction for the two adults who underwent serial scanning. CONCLUSION: The MRI changes in PKU are at least partially reversible by lowering the blood phenylalanine concentration.

Adolescent↗
PubMed1995

The presenting features of mucopolysaccharidosis type IH (Hurler syndrome).

The presenting features of 39 patients with mucopolysaccharidosis (MPS) type IH are described. The mean age at diagnosis was approximately 9 months and it is difficult to see how this can be reduced without consideration of newborn screening. An earlier age at diagnosis is likely to lead to better results following therapy such as bone marrow transplantation. Clinical features which should arouse suspicion of MPS IH include frequent ENT surgery and recurrent herniae. Clinical vigilance is needed for early diagnosis.

Age Factors↗
PubMed1995

Mechanisms for flexibility in DNA sequence recognition and VP16-induced complex formation by the Oct-1 POU domain.

DNA binding by the Oct-1 protein is directed by its POU domain, a bipartite DNA-binding domain made up of a POU-specific (POUS) domain and a POU-homeo (POUH) domain, two helix-turn-helix-containing DNA-binding modules that cooperate in DNA recognition. Although the best-characterized DNA target for Oct-1 binding is the octamer sequence ATGCAAAT, Oct-1 also binds a number of different DNA sequence elements. For example, Oct-1 recognizes a form of the herpes simplex virus VP16-responsive TAATGARAT element, called the (OCTA-)TAATGARAT site, that lacks octamer site similarity. Our studies suggest two mechanisms by which Oct-1 achieves flexible DNA sequence recognition. First, an important arginine found in the Oct-1 POUS domain tolerates substitutions of its base contacts within the octamer site. Second, on the (OCTA-)TAATGARAT site, the POUS domain is located on the side of the POUH domain opposite from where it is located on an octamer site. This flexibility of the Oct-1 POU domain in DNA binding also has an impact on its participation in a multiprotein-DNA complex with VP16. We show that Oct-1 POUS domain residues that contact DNA have different effects on VP16-induced complex formation depending on whether the VP16-responsive element involved has overlapping octamer similarity or not.

Amino Acid Sequence↗
PubMed1995

Absence of acidosis in the initial presentation of propionic acidaemia.

The clinical presentation and results of the initial biochemical and haematological investigations in 11 newborn term infants with propionic acidaemia are described. All patients had neurological symptoms. Only four had clinically important acidosis, but all had a raised blood ammonia. A diagnosis of propionic acidaemia should be considered in all newborn infants with unexplained neurological deterioration even in the absence of a metabolic acidosis.

Acidosis↗
PubMed1994

Magnetic resonance imaging of the brain in phenylketonuria.

Abnormalities of magnetic resonance imaging (MRI) of the brain occur in some patients with phenylketonuria but the clinical importance of this finding is not clear. In order to determine the frequency and functional significance of changes on MRI we investigated 77 adolescent and adult patients with phenylketonuria. Patients aged 14-49 years and taking a restricted diet of 1 g/kg protein underwent clinical examination, IQ testing, neurophysiological investigation, and MRI of the brain. Patients aged between 10-14 years taking a low phenylalanine diet with amino acid supplements had MRI of the brain only. Biochemical control was assessed from: the lifetime blood phenylalanine determined from the mean blood concentration throughout life; the accumulated time for each patient that phenylalanine was < 120 mumol/L; the accumulated time for each patient that phenylalanine was > 1200 mumol/L); mean blood concentration in the first 4 years of life; and the mean blood phe concentration in the 5 years prior to imaging. MRI changes, compatible with a disturbance in the water content of white matter, were present in all but 1 patient. The severity of abnormality was most strongly associated with the blood phenylalanine concentration at the time of imaging. Clinical and neurophysiological abnormalities were less common and usually mild. 3 patients had prolonged central motor conduction time, 7 had prolonged visual evoked potentials, and 5 had impaired peripheral sensory nerve conduction. There was no significant association between the extent of MRI abnormalities and IQ, and the presence of neurophysiological, or clinical abnormalities. An abnormal brain scan in PKU may reflect present biochemical control rather than indicate significant neurological damage. As yet there is little evidence that in most patients with PKU these MRI changes are of clinical importance.

Adolescent↗
PubMed1993

Differential positive control by Oct-1 and Oct-2: activation of a transcriptionally silent motif through Oct-1 and VP16 corecruitment.

Transcriptional regulation by the ubiquitous human POU homeo domain protein Oct-1 and the related B-cell protein Oct-2 is a model for understanding how proteins that recognize the same regulatory site elicit different programs of gene transcription. Here, we describe a mechanism for differential promoter activation whereby only Oct-1, through selective corecruitment with the herpesvirus trans-activator VP16, acquires the ability to stimulate transcription from a TAATGARAT-containing site that responds to neither Oct-1 nor Oct-2 alone. To measure differential in vivo activation by human Oct-1 and Oct-2 in response to VP16, we have developed a transient assay in murine NIH-3T3 cells. Surprisingly, murine Oct-1 associates with VP16 much less effectively than its human counterpart, most likely because the murine Oct-1 homeo domain differs at four positions from the human Oct-1 homeo domain. The murine cell transient assay shows directly that human Oct-1, but not human Oct-2, can respond to VP16 in vivo. The Oct-1 DNA-binding POU domain is sufficient and the Oct-1 homeo domain is critical for this response, because an Oct-1 POU domain containing the Oct-2 homeo domain fails to respond to the VP16-induced positive control of transcription. Thus, by selective homeo domain interaction and corecruitment to an otherwise silent regulatory element, VP16 expands the repertoire of sites responsive to Oct-1 without affecting the activity of its close relative Oct-2.

3T3 Cells↗
PubMed1992

A single amino acid exchange transfers VP16-induced positive control from the Oct-1 to the Oct-2 homeo domain.

The selective association of the herpesvirus trans-activator VP16 with the human Oct-1 homeo domain is a model for differential positive transcriptional control by homeo domains. VP16 discriminates between the closely related homeo domains of Oct-1 and Oct-2 by distinguishing among their seven amino-acid differences; these differences lie on the surface that is thought to be accessible when the homeo domain is bound to DNA. Only two of these seven differences are recognized by VP16, one in each of the first two alpha-helices of the tri-alpha-helical homeo domain. The major determinant for selective association with VP16 in vitro and VP16-induced positive control in vivo is a single glutamic acid residue at position 22 in the first alpha-helix of the Oct-1 homeo domain, but the acidic properties of this residue are not critical for association with VP16 in vitro or in vivo, because it can be replaced by glutamine with little or no deleterious effect. Mere replacement of the single corresponding alanine residue in the Oct-2 homeo domain with the key glutamic acid residue is sufficient to confer on the Oct-2 homeo domain the ability to associate with VP16 in vitro and respond to VP16-induced positive control in vivo. Thus, the specificity of homeo domain positive control can be conferred by a single amino acid difference.

Amino Acid Sequence↗