Eiji Nanba

Anxiety traits associated with a polymorphism in the serotonin transporter gene regulatory region in the Japanese.

AbstractWe determined polymorphism in the serotonin (5-HT) transporter gene-linked polymorphic region (5-HTTLPR) in 501 healthy Japanese, individuals, using the polymerase chain reaction of Lesch et al., with minor modifications. The distribution of allele frequencies was determined and found to differ from that in Caucasians. We also investigated the relationship of polymorphism in 5-HTTLPR to anxiety traits, by having 189 of the 501 subjects complete a self-rating questionnaire for anxiety and depression. Subjects with the short/short (s/s) genotype had significantly higher anxiety scores than those with the long/long (l/l) or l/s genotype. It is suggested that populations with the s/s genotype of 5-HTTLPR have stronger anxiety-related personality traits than those with the l allele.

Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex

AbstractWe have surveyed the mutations of TSC1 and TSC2 from 38 (25 sporadic, 11 familial, and 2 unknown) Japanese patients with tuberous sclerosis complex. In 23 of 38 subjects, we detected 18 new mutations in addition to 4 mutations that had been previously reported. We also found 3 new polymorphisms. The mutations were not clustered on a particular exon in either of the genes. Seven TSC1 mutations found in 3 familial and 4 sporadic cases were on the exons (3 missense, 2 nonsense point mutations, a 1-base insertion, and a 2-bp deletion). Fifteen TSC2 mutations were found in 5 familial cases, 10 sporadic cases, and 1 unknown case. The 12 mutations were on the exons (8 missense, 1 nonsense point mutations, a 1-bp insertion, a 5-bp deletion, and a 4-bp replacement) and 3 point mutations were on the exon-intron junctions. Although the patients with TSC2 mutations tend to exhibit relatively severe mental retardation in comparison to those with TSC1 mutations, a genotype-phenotype correlation could not yet be established. The widespread distribution of TSC1/TSC2 mutations hinders the development of a simple diagnostic test, and the identification of individual mutations does not provide the prediction of prognosis.

A novel interstitial deletion of KAL1 in a Japanese family with Kallmann syndrome

AbstractWe identified a novel interstitial deletion that spanned from exons 5 to 10 of KAL1 in two Japanese brothers with X-linked Kallmann syndrome (KS; MIM no. 308700). Both brothers had hypogonadism, unilateral renal agenesis, and disturbance of the sense of smell, but they had no other neurological manifestations, including mental disturbance. Their mother was confirmed to be an asymptomatic carrier, by use of a comparative multiplex polymerase chain reaction (PCR) analysis. The present patients are further examples of patients with KS without mental disturbance caused by a mutation confined to KAL1.

DEFECT 11 syndrome associated with agenesis of the corpus callosum

Editor—A total of 15 cases of DEFECT 11 syndrome (MIM 601224) have been reported to date.1-8 It is a rare contiguous gene syndrome caused by a deletion in the 11p13-p11 region.6 The main clinical manifestations of the syndrome include multiple exostoses (EXT), enlarged parietal foramina (foramina parietalia permagna, FPP), craniofacial dysostosis, and mental retardation. Various minor features have been described, such as small penis, seizures, hypotonia, obesity, simian creases, epicanthus, and telecanthus.6 Recently, we encountered a Japanese patient who had EXT, FPP, and other associated findings of DEFECT 11 syndrome. An unusual finding seen in our patient was agenesis of the corpus callosum (ACC, MIM 217990). The patient is the third child of a non-consanguineous marriage. Both parents are healthy and other family members have no medical problem. He was born at 32 weeks of gestation because of maternal pre-eclampsia. At birth, he weighed 1095 …

SSCP analysis by RT‐PCR for the prenatal diagnosis of Niemann‐Pick disease type C

The molecular prenatal diagnosis of Niemann‐Pick disease type C (NPC) is presented. The proband with a late infantile type of NPC was a compound heterozygote of a paternal missense mutation, T529G, and a maternal 2 bp deletion at nt 350 of the NPC1 gene. These mutations were detected by single‐strand conformation polymorphism (SSCP) analysis of RT‐PCR products. When the proband was aged 4 years 3 months, prenatal diagnosis for the second child was performed using both biochemical and molecular methods. SSCP analysis for the parental mutations using cDNA from cultured amniotic fluid cells revealed the absence of both mutations and the fetus was diagnosed as being unaffected. This diagnosis was supported by a normal level of cholesterol esterification using cultured amniotic fluid cells. After the childs birth, when he was 21 months old, the diagnosis was confirmed by SSCP analysis of genomic DNAs of his family. This analysis also revealed a unique variation of intron 13, IVS13+753–758 del TTTTTT, that was shared only by the proband and the father, and was suspected as being linked to the T529G missense mutation. A combination of both biochemical and molecular analyses is very useful and reliable for prenatal diagnosis of Niemann‐Pick disease type C. Copyright

Congenital myotonic dystrophy: report of paternal transmission.

A female neonate born to a healthy mother was hospitalized because of enlargement of the lateral ventricles, muscle weakness, irregular respiration, and poor sucking. Characteristic facial appearance such as high forehead and carp mouth were noted. The father had mild manifestations of adult type myotonic dystrophy, including muscle weakness of the extremities, percussion myotonia and atrophy of the facial muscles. PCR analysis and southern blot analysis revealed that CTG repeats in the myotonic dystrophy gene of the infant and the father were about 1000 and 400, respectively. This is a rare case showing paternally transmitted congenital myotonic dystrophy and seems to be the first report describing a neonate.

Sonic hedgehog signal peptide mutation in a patient with holoprosencephaly

We investigated the molecular basis of holoprosencephaly in a sporadic patient and identified a novel missense mutation in the signal sequence of the sonic hedgehog (Shh) gene. Magnetic resonance imaging of the head showed a lobar type of holoprosencephaly and partial agenesis of the anterior corpus callosum. He was treated for craniosynostosis at 7 months of age. All three exons of the Shh gene were amplified by polymerase chain reaction from genomic DNA of the patient and controls. Sequencing analysis of the polymerase chain reaction fragments, screened by single‐strand conformation polymorphism analysis, revealed a heterozygous mutation of a T‐to‐C substitution at nucleotide position 50. This mutation predicted an amino acid replacement of leucine to proline at codon 17 located in the signal peptide of SHH protein. It probably disturbs the translocation of the protein into the endoplasmic reticulum and may lead to holoprosencephaly because of haploinsufficiency of Shh. Ann Neurol 2000;47:514–516.

Novel TSC2 mutation in a patient with pulmonary tuberous sclerosis: lack of loss of heterozygosity in a lung cyst

A Japanese patient with tuberous sclerosis (TSC), who manifested with multiple lung cysts and pneumothorax, is described. All exons of two TSC genes, TSC1 and TSC2, in peripheral blood leukocytes from the patient were analyzed by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). A novel T-to-G transition was found in exon 19 of TSC2 at nucleotide position 2168. This mutation caused an amino acid change, L717R. There was no such mutation in any other family members or in 100 normal Japanese. An automated sequencer-assisted quantitative analysis of normal and mutated SSCP-bands revealed no loss of heterozygosity (LOH) in the lung cyst tissue of the patient.

Fibrillin gene ( FBN1 ) mutations in Japanese patients with Marfan syndrome

AbstractMarfan syndrome (MFS; MIM #154700) is a connective tissue disorder characterized by cardiovascular, skeletal, and ocular abnormalities. The fibrillin-1 gene (FBN1; MIM no. 134797) on chromosome 15 was revealed to be the cause of Marfan syndrome. To date over 137 types of FBN1 mutations have been reported. In this study, two novel mutations and a recurrent de-novo mutation were identified in patients with MFS by means of single-strand conformational polymorphism (SSCP) analysis. The two novel mutations are a 4-bp deletion at nucleotide 2820-2823 and a G-to-T transversion at nucleotide 1421 (C474F), located on exon 23 and exon 11, respectively. A previously reported mutation at the splicing donor site of intron 2 (IVS2 G + 1A), which is predicted to cause exon skipping, was identified in a sporadic patient with classical MFS.