Mutations in KAL-1 gene of Kallmann Syndrome cases in NTU Hospital
Date Issued
2009
Date
2009
Author(s)
Wu, Che-Tsung
Abstract
Kallmann syndrome is a developmental disorder characterized by idiopathic hypothalamic hypogonadotropic hypogonadism with olfactory loss (anosmia or hyposmia：with low or poor sense of smell). These patients have delayed or absent puberty due to deficiency of hypothalamic gonadotropin-releasing hormone (GnRH), resulting in low secretion or absence of pituitary luteinizing hormone (LH), follicle-stimulating hormone (FSH). Even though the normal level of LH and FSH secretion may exist, there is no response or delayed response in sex hormone secretion from the gonads of these patients. These result in insufficient secretion of testosterone in male or ovarian secretion of estradiol in female. Currently this syndrome can be divided into four types, KAL1, caused by mutations in the KAL-1 gene located on X chromosome Xp22.3 and inherited in an X-linked recessive mode; KAL2, caused by mutations in FGFR; KAL3, caused by mutations in PROKR2 gene, and KAL4, caused by mutations in PROK2 genes. The KAL2 and KAL4 are inherited in an autosomal dominant mode except KAL3. n this study, we have collected a total number of eight patients with Kallmann syndrome in the clinics of Internal Medicine and the Pediatric Endocrine special clinic, in National Taiwan University Hospital. One was a 25-year-old female, and the other seven were males with their age range 19-45, and one 5-year-old boy. In this thesis, searching for mutations among these Kallmann syndrome patients were focused on the KAL-1 gene first. In order to delineate the functional mutations of KAL-1 genes among these patients, sequence analysis of all 14 exons in KAL-1 gene was performed. We found that two point mutations within the coding sequence (CDS) region in patients (subjects) 1, 2, 3, 5, 7, 8. These two mutations were in the exon 11 (c.1600G>A) and exon 12 (c.1833C>T), leading to the Val534Ile missense mutation and a synonymous mutation (Ile611). There were more mutations found in exon 14 of the Subject 5 in addition to the previous two point mutations. They were c.1997A>T (Lys666Met), c.2003G>A (Arg668His), *19G>T and *21G>A, and the latter two have been beyond the termination code in the 3 ''end. ubject 6 was a 5-year-old boy with a total of 37 mutations from exon 11 (at the junction between Intron 10 and exon 11) to the exon 14. It might arise from the possible incorrect amplification of the fragments from the pseudogene KALP which is homologue of KAL-1 on Y located in Yq11.2 by PCR reaction, instead of truly amplifying the real exon11-14 of KAL-1 on X chromosome.e did not find any mutations in the sequence of Subject 4 in KAL-1.
Subjects
Kallmann syndrome
gonadotropin releasing hormone
anosmia
idiopathic hypogonadotropic hypogonadism
SDGs
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