Disease relevance of KAL1

• The product of X-linked Kallmann's syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons [1].
• Clinical assessment in the 15 males with KAL1 mutations showed normal and borderline olfactory function in two males and right-side dominant renal lesion in seven males, in addition to variable degrees of hypogonadotropic hypogonadism (HH) in all the 15 males and olfactory dysfunction in 13 males [2].
• Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in one female, cleft palate in one male, cleft palate and perceptive deafness in one male, and dental agenesis and perceptive deafness in one male, in addition to a variable extent of HH and olfactory dysfunction [2].
• We characterized the clinical findings and molecular analysis of GnRHR and KAL1 genes in 26 Brazilian males with IHH with and without hyposmia/anosmia [3].
• Analysis of an interstitial deletion in a patient with Kallmann syndrome, X-linked ichthyosis and mental retardation [4].

Psychiatry related information on KAL1

• In a human condition, Kallmann syndrome, the data show a clear, indirect genetic influence on an important human social behavior, in which damage at chromosome Xp-22.3 works through at least six discrete steps to affect libido [5].
• The KSV model of the schizophrenias proposes that up to 70% of schizophrenics have a pathogenic allele, or abnormal expression, of the KALIG-1 gene which is located at Xp22 [6].
• KAL, a gene mutated in Kallmann's syndrome, is expressed in the first trimester of human development [7].
• In addition to being aware of the variable presentation of cognitive and behavioral characteristics in those already diagnosed, it is important to consider KMS when assessing dysmorphic children with learning disabilities and/or autism [8].
• Of those patients with Kallmann syndrome, 5/19 reported mild depressive symptoms only, all resolving with testosterone replacement [9].

High impact information on KAL1

• Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome [10].
• Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males [10].
• We took advantage of overlapping interstitial deletions at chromosome 8p11-p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2 [10].
• In the developing and adult chicken, high levels of expression were found in the mitral cells of the olfactory bulb (the target of olfactory axons) and in the Purkinje cells of the cerebellar cortex, both areas affected in patients with Kallmann syndrome [11].
• Kallmann syndrome is a genetic disorder characterized by a defect in olfactory system development, which appears to be due to an abnormality in the migration of olfactory axons and gonadotropin releasing hormone (Gn-RH) producing neurons [11].

Chemical compound and disease context of KAL1

• Deletions of the steroid sulphatase gene in "classical" X-linked ichthyosis and in X-linked ichthyosis associated with Kallmann syndrome [12].
• CONCLUSIONS: T1-weighted MR examination of the inferior frontal region in the coronal plane can help determine whether a patient with hypogonadotropic hypogonadism, with or without clinically evident anosmia, is afflicted with Kallmann syndrome [13].
• We describe a 14 year old girl with KMS exhibiting chronic idiopathic thrombocytopenic purpura (chronic ITP), including immunological studies [14].

Biological context of KAL1

• Deletions or point mutations of a gene located at Xp22.3 (KAL1) are responsible for the disease [1].
• PCR of the 14 exons of the KAL1 gene was performed on genomic DNA [15].
• The duplication of nucleotides in exon 1 is located in the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif, affecting the KAL1 protein either by interrupting the normal transcription or stopping the translation at the stop codon [15].
• The gene responsible for the X-chromosome linked form of the disease (KAL1) has been identified in 1991 [16].
• KAL1 encodes anosmin-1, an approximately 95-kDa glycoprotein of unknown function which is present locally in various extracellular matrices during the period of organogenesis [16].

Anatomical context of KAL1

• Specifically, we exposed immortalized migrating GnRH neurons (GN11 cells) to conditioned media (CM) of COS or CHO cells transiently transfected with human KAL1 gene in microchemotaxis and collagen gel assays [1].
• This low prevalence of KAL1 mutations indicates that other genes, such as the fibroblast growth factor receptor 1 (FGFR1) gene or other as yet undiscovered genes, epigenetic events and/or environmental factors might be involved in the aetiology and phenotypic variability of KS [3].
• KS was evident with hypogonadotropic hypogonadism, hyposmia and a hypoplastic anlage of the olfactory tract in magnetic resonance imaging [4].
• Abnormalities of olfactory bulbs/sulci were observed in 79% of KS patients [3].
• When demethylation was induced in cell lines with their methylation by 5-aza-2'-deoxycytidine, expression of ZIK1, KAL1, and FGF14 was restored, supporting causal roles of methylation in their silencing [17].

Associations of KAL1 with chemical compounds

• Coexistence of Kallmann syndrome and complete androgen insensitivity in the same patient [18].
• The proband presented at age 18 yr with KS and was subsequently treated with testosterone (T) therapy [19].
• Finally, anosmin-1 (the product of the gene responsible of the X-linked form of Kallmann's disease) was found to induce a significant chemotactic response of GN11 cells, confirming a permissive/instructive role of KAL1 gene product in the migratory behaviour of GnRH neurons [20].
• In addition, the combination of CADA with the gp41 fusion inhibitor T-20 (enfuvirtide), the CXCR4 antagonist AMD3100 and the gp120-specific interacting plant lectins from Galanthus nivalis (GNA) and Hippeastrum hybrid (HHA) also resulted in a synergistic inhibition [21].
• CONCLUSIONS: A patient bearing a contiguous gene syndrome with partial deletion of the Kallmann syndrome gene and complete deletion of the steroid sulphatase gene is described [22].

Physical interactions of KAL1

• C. elegans Kallmann syndrome protein KAL-1 interacts with syndecan and glypican to regulate neuronal cell migrations [23].

Regulatory relationships of KAL1

• FGFR1 loss-of-function mutations were reported in Kallmann syndrome whereas inactivating mutations of GPR54 were described in the idiopathic form of the gonadotropic deficiency [24].

Other interactions of KAL1

• The last novel mutation, a stop codon in exon 6, is located within the region encoding the first fibronectin type III-like repeat of the KAL1 protein [15].
• Clinical assessment and molecular analysis of GnRHR and KAL1 genes in males with idiopathic hypogonadotrophic hypogonadism [3].
• In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual [25].
• 3. Four human YAC libraries were screened initially with sequences from DXS237 (GMGX9), DXS278 (S232B), and KAL and later with primers from exon 10 of the STS gene and the end fragment of a YAC clone YGX3 to fill the gaps [26].
• The gene for the X-linked Kallmann syndrome (KAL), a developmental disorder characterized by hypogonadotropic hypogonadism and anosmia, maps to Xp22.3 and has a homologous locus, KALP, on Yq11 [27].

Analytical, diagnostic and therapeutic context of KAL1

• KAL1 sequence analysis identified two novel missense mutations: c.1061A to G in exon 7 (N304S) and c.1583C to A in exon 10 (S478X) [3].
• In 2 families, large Xp22.3 deletions, both including the entire KAL gene, have been detected by Southern blot analysis [28].
• Detection of KAL-1 gene deletion with fluorescence in situ hybridization [29].
• A state-of-the-art review of a widely-used health promotion technique, the health hazard/health risk appraisal (HHA/HRA), was conducted [30].
• By immunohistofluorescence and immunoelectron microscopy, we establish that the KAL-1 encoded protein, anosmin-1, is a transient and regionally restricted component of extracellular matrices during organogenesis in man [31].

References