Duke, Veronique Michal; (1996) X-linked kallman's syndrome: a molecular genetic and developmental analysis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Kallmann's syndrome (KS) is defined as the association of hypogonadotrophic hypogonadism (IHH), caused by hypothalamic gonadotrophin releasing hormone (GnRH) deficiency, and anosmia, due to malformation of the olfactory bulbs and tracts. Patients most commonly present with delayed puberty and may also present in childhood with cryptorchidism. Renal agenesis seen in 40% and synkinesis observed in up to 90[percent] of patients with X-linked KS (XKS) are likely to originate in the aberrant expression of KAL (Xp22.3) during early foetal development. Failure of the olfactory axons in the accessory olfactory nerves to project through the cribriform plate and establish synaptic contact with the developing olfactory bulb is thought to be central to the pathogenesis of these clinical features. GnRH neurons originating in the primitive nasal area consequently fail to migrate into the forebrain because of the absence of the "scaffolding" provided by these olfactory nerves. This study has examined areas of KAL protein (680 amino acid protein containing a signal peptide but no membrane insertion or anchorage sequence, suggesting that this is a secreted protein) expression in the developing foetus and adult using anti-protein peptide antibodies generated in mice. A short sequence of the putative KAL sequence was used to synthesise a multiple antigenic peptide, which was then used as the antigen. Due to the non specificity of these antibodies the areas and stages of KAL gene expression were further investigated using in situ hybridisation and reverse transcriptase polymerase chain reaction (RT-PCR) on first trimester foetal tissue. This revealed KAL transcript in the olfactory bulbs, neuroretina and developing kidney. Patients with XKS and sporadic KS were investigated for mutations in KAL using established molecular biology techniques including PCR, direct DNA sequencing and single stranded conformational polymorphism (SSCP). Previously characterised mutations were confirmed and two new mutations identified. Using restriction fragment length polymorphism (RFLP) analysis, a methodology was established to successfully screen XKS earners in a selection of patient pedigrees.

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