Two Autopsied Cases of Kallmann's Syndrome With Dysplasia of the Hippocampus

Itoh, Masayuki; Houdou, Sadataka; Mizushima, Minoru; Tokita, Yasuko; Kawahara, Hiromu; S, Ishii; Ohama, Eisaku

doi:10.1177/088307389701200809

Cited by 5 publications

(2 citation statements)

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“…Independent of their neurochemical characteristics, NMR of Kallmann's syndrome patients do not show changes in the volume or shape of this region (Yousem et al,1993,1996). Indeed, there is only one report of two KS patients, but with a severe mental retardation, who showed dysplasia of the hippocampus (Itoh et al,1997). It is difficult to think that the loss of the small proportion of Anos1‐immunopositive neurons observed within the hippocampus could exclusively be the cause for that conspicuous morphological alteration; it seems more plausible that it could reflect a more general developmental disorder.…”

Section: Resultsmentioning

confidence: 99%

Expression pattern of Anosmin‐1 during pre‐ and postnatal rat brain development

Clemente

Esteban

Valle

et al. 2008

Developmental Dynamics

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Anosmin-1 participates in the development of the olfactory and GnRH systems. Defects in this protein are responsible for both the anosmia and the hypogonadotrophic hypogonadism found in Kallmann's syndrome patients. Sporadically, these patients also manifest some neurological symptoms that are not explained in terms of the developmental defects in the olfactory system. We describe the pattern of Anosmin-1 expression in the central nervous system during rat development using a novel antibody raised against Anosmin-1 (Anos1). The areas with Anos1-stained neurons and glial cells were classified into three groups: (1) areas with immunoreactivity from embryonic day 16 to postnatal day (P) 15; (2) areas with Anosmin-1 expression only at postnatal development; (3) nuclei with immunoreactivity only at P15. Our data show that Anos1 immunoreactivity is detected in projecting neurons and interneurons within areas of the brain that may be affected in patients with Kallmann's syndrome that develop both the principal as well as sporadic symptoms. Developmental Dynamics 237:2518 -2528, 2008.

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Section: Resultsmentioning

confidence: 99%

Expression pattern of Anosmin‐1 during pre‐ and postnatal rat brain development

Clemente

Esteban

Valle

et al. 2008

Developmental Dynamics

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“…In addition, the present study suggests that loss-of-function mutations in the Jacob/Nsmf gene are likely to cause selective cognitive dysfunction in humans. Of interest in this regard is a report on hippocampal dysplasia in two cases of KS [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis

et al. 2016

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Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element-binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Here we show that mice that are constitutively deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, these mice exhibit hippocampal dysplasia with a reduced number of synapses and simplification of dendrites, reduced hippocampal long-term potentiation (LTP) at CA1 synapses and deficits in hippocampus-dependent learning. Brain-derived neurotrophic factor (BDNF) activation of CREB-activated gene expression plays a documented role in hippocampal CA1 synapse and dendrite formation. We found that BDNF induces the nuclear translocation of Jacob in an NMDAR-dependent manner in early development, which results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. Nsmf knockout (ko) mice show reduced hippocampal Bdnf mRNA and protein levels as well as reduced pCREB levels during dendritogenesis. Moreover, BDNF application can rescue the morphological deficits in hippocampal pyramidal neurons devoid of Jacob. Taken together, the data suggest that the absence of Jacob in early development interrupts a positive feedback loop between BDNF signaling, subsequent nuclear import of Jacob, activation of CREB and enhanced Bdnf gene transcription, ultimately leading to hippocampal dysplasia.

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