Masato Tsukahara

Imprinting of human GRB10 and its mutations in two patients with Russell-Silver syndrome.

Documentation of maternal uniparental disomy of chromosome 7 in 10% of patients with Russell-Silver syndrome (RSS), characterized by prenatal and postnatal growth retardation and dysmorphic features, has suggested the presence of an imprinted gene on chromosome 7 whose mutation is responsible for the RSS phenotype. Human GRB10 on chromosome 7, a homologue of the mouse imprinted gene Grb10, is a candidate, because GRB10 has a suppressive effect on growth, through its interaction with either the IGF-I receptor or the GH receptor, and two patients with RSS were shown to have a maternally derived duplication of 7p11-p13, encompassing GRB10. In the present study, we first demonstrated that the GRB10 gene is also monoallelically expressed in human fetal brain tissues and is transcribed from the maternally derived allele in somatic-cell hybrids. Hence, human GRB10 is imprinted. A mutation analysis of GRB10 in 58 unrelated patients with RSS identified, within the N-terminal domain of the protein, a P95S substitution in two patients with RSS. In these two cases, the mutant allele was inherited from the mother. The fact that monoallelic GRB10 expression was observed from the maternal allele in this study suggests but does not prove that these maternally transmitted mutant alleles contribute to the RSS phenotype.

Sotos syndrome and haploinsufficiency of NSD1: clinical features of intragenic mutations and submicroscopic deletions

Sotos syndrome (MIM 117550) is a congenital developmental disorder characterised by overgrowth and advanced bone age in infancy to early childhood, mental retardation, and various minor anomalies such as macrocephaly, prominent forehead, hypertelorism, downward slanting palpebral fissures, large ears, high and narrow palate, and large hands and feet.1,2 It is also frequently associated with brain, cardiovascular, and urinary anomalies3–6 and is occasionally accompanied by malignant lesions such as Wilms tumour and hepatocarcinoma.7,8 This condition has been classified as an autosomal dominant disorder, because several familial cases consistent with dominant inheritance have been described previously.9 Thus, sporadic cases accounting for most of the Sotos syndrome patients are assumed to be the result of de novo dominant mutations. We have recently shown that Sotos syndrome is caused by haploinsufficiency of the gene for NSD1 (nuclear receptor binding Su-var, enhancer of zeste, and trithorax domain protein 1).10 NSD1 consists of 23 exons and encodes at least six functional domains possibly related to chromatin regulations (SET, PWWP-I, PWWP-II, PHD-I, PHD-II, and PHD-III), in addition to 10 putative nuclear localisation signals.11 It is expressed in several tissues including fetal/adult brain, kidney, skeletal muscle, spleen, and thymus11 and is likely to interact with nuclear receptors as a bifunctional transcriptional cofactor.12 In this paper, we report on clinical findings in Japanese patients with proven point mutations in NSD1 and those with submicroscopic deletions involving the entire NSD1 gene and discuss genotype-phenotype correlation. This study consisted of five patients with heterozygous NSD1 point mutations and 21 patients with heterozygous submicroscopic deletions involving the entire NSD1 gene. The mutations were identified by direct sequencing of exons 2–23 and their flanking introns covering the whole coding region of NSD1 ,11 using genomic DNA extracted from peripheral leucocytes or …

Novel and recurrent EBP mutations in X-linked dominant chondrodysplasia punctata

Chondrodysplasia punctata (CDP) is a heterogeneous group of skeletal dysplasias characterized by stippled epiphyses. A subtype of CDP, X-linked dominant chondrodysplasia punctata (CDPX2), known also as Conradi-Hünermann-Happle syndrome, is a rare skeletal dysplasia characterized by short stature, craniofacial defects, cataracts, ichthyosis, coarse hair, and alopecia. The cause of CDPX2 was unknown until recent identification of mutations in the gene encoding Delta(8),Delta(7) sterol isomerase emopamil-binding protein (EBP). Twelve different EBP mutations have been reported in 14 patients with CDPX2 or unclassified CDP, but with no evidence of correlation between phenotype and nature of the mutation. To characterize additional mutations and investigate possible phenotype-genotype correlation, we sequenced the entire EBP gene in 8 Japanese individuals with CDP; 5 of them presented with a CDPX2 phenotypes. We found EBP mutations in all 5 CDPX2 individuals, but none in non-CDPX2 individuals. Three of these CDPX2 individuals carried novel nonsense mutations in EBPand the other two, separate missense mutations that had been reported also in different ethnic groups. Our results, combined with previous information, suggest all EBP mutations that produce truncated proteins result in typical CDPX2, whereas the phenotypes resulted from missense mutations are not always typical for CDPX2. Patients with nonsense mutations showed abnormal sterol profiles consistent with a defect in Delta(8), Delta(7) sterol isomerase. X-inactivation patterns of the patients showed no skewing, an observation that supports the assumption that inactivation of the EBP gene occurs at random in affected individuals.

Dubowitz syndrome: review of 141 cases including 36 previously unreported patients.

We review clinical information on 141 individuals with Dubowitz syndrome, 105 reported since 1965, and 36 previously unreported. We define the Dubowitz syndrome phenotype on the basis of clinical descriptions. The facial appearance is characteristic and present in most patients with Dubowitz syndrome. The phenotypic spectrum is quite variable and ranges from normal growth and head circumference with mild psychomotor retardation and lack of eczema to a condition of severe growth retardation, mental retardation, microcephaly, and eczema. Overall, the condition may involve the cutaneous, ocular, dental, digestive, musculoskeletal, urogenital, cardiovascular, neurological, hematological, and immune systems. Characteristic behavior patterns which have not been cited previously are present in our cases; most patients are hyperactive, shy, hate crowds, and like music, rhythm, and vibrations from music speakers, tape recorders, or transmitted through floors. Dubowitz syndrome is an autosomal recessive disorder with possibly increased frequency of parental consanguinity. Heterogeneity cannot be excluded at this time.

Subtelomere specific microarray based comparative genomic hybridisation: a rapid detection system for cryptic rearrangements in idiopathic mental retardation

Mental retardation (MR) occurs in 2–3% of the general population, and more than half of MR patients are categorised as idiopathic—that is, the cause is unknown.1,2 Patients with idiopathic MR are presumed to be affected with certain genetic disorders or undetectable chromosomal abnormalities. MR may also be caused by environmental factors independently or by their interaction with genetic factors. Subtelomeric rearrangements comprise about half of segmental aneusomies,3 and are one of the major causes of MR.4,5 A recent review showed that subtelomeric rearrangements were detected in 131 (5.1%) of 2585 children with MR.1,4–6 Conventional cytogenetic analysis can detect many, but not all, rearrangements, depending on its powers of resolution.4 Other methods, such as fluorescent in situ hybridisation (FISH) using a complete set of subtelomeric probes, multicolour FISH (M-FISH), comparative genomic hybridisation (CGH), spectrum karyotyping, multiple amplifiable probe hybridisation, primed in situ labelling, and genotyping have been designed to detect subtelomeric rearrangements, but none of them is ideal in terms of sensitivity and/or efficiency.4,6 Microarray based CGH is a promising, high throughput method of detecting subtelomeric rearrangements.4 Veltman et al recently reported a microarray CGH system using crude bacterial/plasmid derived artificial chromosome (BAC/PAC) DNA for the analysis of subtelomeric aberrations, and suggested that degenerate oligonucleotide primed (DOP)-PCR products could also be used instead of crude clone DNA, although the performance of DOP-PCR products might be less sensitive.7 We have developed a microarray CGH system to identify rearrangements involving a subtelomeric region, using DOP-PCR that amplifies subtelomeric BAC/PAC DNA. Here we describe details of the method and the results of microarray CGH analyses of five cases of Wolf-Hirschhorn syndrome (WHS) associated with terminal 4p deletions as positive controls, and of 69 patients with idiopathic MR with or without multiple …

Dominant inheritance of Kabuki make-up syndrome

We report on a total of 4 individuals in 2 families with Kabuki make-up syndrome. In family 1, the proposita, a 2 4/12-year-old girl and her mother had typical Kabuki make-up syndrome. The proposita also had early breast development. In family 2, the proposita, a 6-month-old girl and her mother had typical Kabuki make-up syndrome. The proposita died at age 6 months. Analysis of 2 families indicates that the condition is an autosomal dominant inheritance with variable expressivity.

Preferential Paternal Origin of Microdeletions Caused by Prezygotic Chromosome or Chromatid Rearrangements in Sotos Syndrome

Sotos syndrome (SoS) is characterized by pre- and postnatal overgrowth with advanced bone age; a dysmorphic face with macrocephaly and pointed chin; large hands and feet; mental retardation; and possible susceptibility to tumors. It has been shown that the major cause of SoS is haploinsufficiency of the NSD1 gene at 5q35, because the majority of patients had either a common microdeletion including NSD1 or a truncated type of point mutation in NSD1. In the present study, we traced the parental origin of the microdeletions in 26 patients with SoS by the use of 16 microsatellite markers at or flanking the commonly deleted region. Deletions in 18 of the 20 informative cases occurred in the paternally derived chromosome 5, whereas those in the maternally derived chromosome were found in only two cases. Haplotyping analysis of the marker loci revealed that the paternal deletion in five of seven informative cases and the maternal deletion in one case arose through an intrachromosomal rearrangement, and two other cases of the paternal deletion involved an interchromosomal event, suggesting that the common microdeletion observed in SoS did not occur through a uniform mechanism but preferentially arose prezygotically.

Occipital horn syndrome: report of a patient and review of the literature.

We report an 18‐year‐old boy with occipital horn syndrome and we review the 20 cases previously published with this syndrome. The distinctive features common to all patients were unusual facial appearance, skeletal abnormalities, chronic diarrhea and genitourinary abnormalities. The skeletal abnormalities included occipital horns, short, broad clavicles, deformed radii, ulnae, and humeri, narrowing of the rib cage, undercalci‐fied long bones with thin cortical walls and coxa valga. Occipital horn syndrome is inherited in an X‐linked recessive fashion. Our analysis indicates that occipital horn syndrome is associated with a recognizable characteristic phenotype.

Familial isolated noncompaction of ventricular myocardium

AbstractWe report a family in which two male sibs were affected with isolated noncompaction of ventricular myocardium (INVM). The familial occurrence of INVM suggests a genetic basis. We review the literature of familial and nonfamilial cases and discuss the inheritance pattern of INVM.

Leukocyte adhesion deficiency: Identification of novel mutations in two japanese patients with a severe form

Leukocyte adhesion deficiency is a disorder with mutations of the gene for the beta subunit, a component common to three adhesion molecules; LFA-1, Mac-1 and p150,95. The molecular basis of the disorder was studied in two patients with its severe form. In the first patient, the mutant gene expressed an aberrant mRNA, 1.2 kb longer than usual, resulting from a G to A substitution at the splice donor site of a 1.2 kb intron. Several aberrantly spliced messages, arising from splicing at cryptic donor sites, were also identified. The beta subunit proteins deduced from the mRNA sequences lacked half the carboxyl terminal portion. In the second patient, the mutation was a G to A transition at nucleotide 454, which resulted in an Asp128 to Asn substitution of the beta subunit. The 128th Asp residue is located in a region crucial for the association with alpha subunits and strictly conserved among the integrin beta subunits so far analyzed.