Bernard, Tanya; (1998) Investigation of the molecular pathogenesis of Kostmann's syndrome. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Deletion mutants of the intracytoplasmic domain of the granulocyte colony-stimulating factor receptor (G-CSFR) have shown that the membrane-proximal region is essential for transduction of a mitotic signal and that the C-terminal region appears to be necessary for transduction of cell differentiation. Changes in this domain may result in the uncoupling of these two processes as happens in Kostmanns syndrome (KS) and acute leukaemia. Such alterations could occur either as isoforms or mutations. Previously there has been only one report of over-expression of a G-CSFR isoform occurring in a patient with acute myeloid leukaemia (AML) while there have been several reports of mutations within the intracytoplasmic tail of the G-CSFR in KS. Here the reverse transcription-polymerase chain reaction, single strand conformation polymorphism analysis, sequencing and restriction enzyme digestion have been used to study the transmembrane and intracytoplasmic domains of G-CSFR mRNA from peripheral blood or bone marrow of 11 haematologically normal controls, 40 patients with AML and 11 patients with KS (one during transformation to AML). Two novel transcripts were identified in normal myeloid cells. Both were expressed at low levels and neither are predicted to be of physiological significance. There was no evidence of aberrant expression of isoforms in either patient group and only one point mutation was detected in the AML mRNA samples, probably representing a rare polymorphism. Abnormalities of the G-CSFR in AML thus appear to be rare. Two of the patients with KS had mutations in a minor percentage of their transcripts, both resulting in a premature stop codon and truncation of the intracytoplasmic domain of the G-CSFR. In one the mutation remained stable for two years, in the other it was acquired and then spontaneously lost nearly three years later. No mutation could be demonstrated in the child with KS/AML. These mutations do not appear to be implicated either in the pathogenesis of the severe neutropenia or transformation from KS to AML and a new hypothesis as to their significance is suggested.

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