Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair

The association between MSHR coding region variation and hair colour in humans has been examined by genotyping 25 red haired and 62 non-red Caucasians, all of whom were 12 years of age and members of a twin pair study. Twelve amino acid substitutions were seen at 11 different sites, nine of these being newly described MSHR variants. The previously reported Val92Met allele shows no association with hair colour, but the three alleles Arg151Cys, Arg160Trp and Asp294His were associated with red hair and one Val60Leu variant was most frequent in fair/blonde and light brown hair colours. Variant MSHR genotypes are associated with lighter skin types and red hair (P < 0.001). However, comparison of the MSHR genotypes in dizygotic twin pairs discordant for red hair colour indicates that the MSHR gene cannot be solely responsible for the red hair phenotype, since five of 13 pairs tested had both haplotypes identical by state (with three of the five having both identical by descent). Rather, it is likely that additional modifier genes exist, making variance in the MSHR gene necessary but not always sufficient, for red hair production.      

Regional distribution of fiber types in developing baboon diaphragm muscles

Fiber type distribution and mean fiber area were determined for seven sites in diaphragm muscles of premature (140 days gestation), full-term (180 days gestation), and adult baboons. Within a group, data did not differ significantly amongst the seven sites. The diaphragm of premature animals had a large proportion [56(+/- 2)%] of type IIc fibers, smaller proportions of type I, IIo, and IIh fibers [16(+/- 2), 21(+/- 1), and 7(+/- 2)%, respectively], and no type IIg fibers. Full-term animals had fewer type IIc [2(+/- 1)%] fibers, greater proportions of type I [46(+/- 2)%], IIh [23(+/- 1)%], and IIg [11(+/- 1)%] fibers, and a similar proportion of type IIo fibers [17(+/- 1)%]. Diaphragm from adult baboons had similar proportions of type IIh, IIg, and IIc fibers in females [39(+/- 4), 20(+/- 2), 1(+/- 1), 41(+/- 5), and 1(+/- 1)%] and males [48(+/- 2), 16 (+/- 1), 0(+/- 0), 36(+/- 2), and 3(+/- 2)%]. Fiber area for premature [143(+/- 9), 210(+/- 15), 231(+/- 15), and 156(+/- 16) microns2 for type I, IIo, IIh, and IIc fibers], newborn [317(+/- 32), 374(+/- 36), 468(+/- 42), 498(+/- 43), and 322(+/- 37) microns2 for type I, IIo, IIh, IIg, and IIc fibers], and for type I, IIo, IIg, and IIc fibers from adult female [1,759(+/- 130), 2,365(+/- 284), 5,026(+/- 742), and 1,843(+/- 111) microns2] and adult male [2,513(+/- 221), 3,987(+/- 267), 6,102(+/- 376), and 2,833(+/- 151) microns2] baboons indicated growth which correlated with body weight. Our results also show that metabolic and contractile enzymes develop normally, but growth of respiratory muscle fibers is arrested, during 10 days following premature birth.     

Mouse homologues of the human AZF candidate gene RBM are expressed in spermatogonia and spermatids, and map to a Y chromosome deletion interval associated with a high incidence of sperm abnormalities

An RNA-binding motif (RBM) gene family has been identified on the human Y chromosome that maps to the same deletion interval as the 'azoospermia factor' (AZF). We have identified the homologous gene family (Rbm) on the mouse Y with a view to investigating the proposal that this gene family plays a role in spermatogenesis. At least 25 and probably >50 copies of Rbm are present on the mouse Y chromosome short arm located between Sry and the centromere. As in the human, a role in spermatogenesis is indicated by a germ cell-specific pattern of expression in the testis, but there are distinct differences in the pattern of expression between the two species. Mice carrying the deletion Yd1, that maps to the proximal Y short arm, are female due to a position effect resulting in non-expression of Sry ; sex-reversing such mice with an Sry transgene produces males with a high incidence of abnormal sperm, making this the third deletion interval on the mouse Y that affects some aspect of spermatogenesis. Most of the copies of Rbm map to this deletion interval, and the Yd1males have markedly reduced Rbm expression, suggesting that RBM deficiency may be responsible for, or contribute to, the abnormal sperm development. In man, deletion of the functional copies of RBM is associated with meiotic arrest rather than sperm anomalies; however, the different effects of deletion are consistent with the differences in expression between the two species.      

Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD)

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha- synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha- synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.      

Efferent connections of the medial prefrontal cortex in the rabbit

The different cytoarchitectonic regions of the medial prefrontal cortex (mPFC) have recently been shown to play divergent roles in associative learning in rabbits. To determine if these subareas of the mPFC, including areas 24 (anterior cingulate cortex), 25 (infralimbic cortex), and 32 (prelimbic cortex) have differential efferent connections with other cortical and subcortical areas in the rabbit, anterograde and retrograde tracing experiments were performed using thePhaseolus vulgaris leukoagglutinin (PHA-L), and horseradish peroxidase (HRP) techniques. All three areas showed local dorsal-ventral projections into each of the other areas, and a contralateral projection to the homologous area on the other side of the brain. All three also revealed a trajectory through the striatum, resulting in heavy innervation of the caudate nucleus, the claustrum, and a lighter projection to the agranular insular cortex. The thalamic projections of areas 24 and 32 were similar, but not identical, with projections to the mediodorsal nucleus (MD) and all of the midline nuclei. However, the primary thalamic projections from area 25 were to the intralaminar and midline nuclei. All three areas also projected to the ventromedial and to a lesser extent to the ventral posterior thalamic nuclei. Projections were also observed in the lateral hypothalamus, in an area just lateral to the descending limb of the fornix. Amygdala projections from areas 32 and 24 were primarily to the lateral, basolateral and basomedial nuclei, but area 25 also projected to the central nucleus. All three areas also showed projections to the midbrain periaqueductal central gray, median raphe nucleus, ventral tegmental area, substantia nigra, locus coeruleus and pontine nuclei. However, only areas 24 and the more dorsal portions of area 32 projected to the superior colliculus. Area 25 and the ventral portions of area 32 also showed a bilateral projection to the parabrachial nuclei and dorsal and ventral medulla. The dorsal portions of area 32, and all of area 24 were, however, devoid of these projections. It is suggested that these differential projections are responsible for the diverse roles that the cytoarchitectonic subfields of the mPFC have been demonstrated to play in associative learning.     

Recombination aneusomy of chromosome 5 associated with multiple severe congenital malformations

A male infant is described in whom congenital anomalies were recognized prenatally by ultrasound examination. The infant was delivered following spontaneous labor and died approximately 15 min after birth. An autopsy revealed major anomalies in the central nervous system (holoprosencephaly with premaxillary agenesis), the gastrointestinal system (esophageal atresia) and the heart (tetralogy of Fallot). Chromosomal studies revealed recombinant chromosome 5 [46,XY, rec(5), dup q, inv(5)(p15q32)], resulting in partial trisomy 5q and partial monosomy 5p. Cytogenetic investigation of the family revealed a pericentric inversion of chromosome 5 in the father and paternal grandmother, 46,XY (and XX, respectively,) inv(5)(p15q32). The congenital anomalies in this infant are more extensive and severe than previously reported in cases of recombination aneusomy involving chromosome 5.     

Suprabasal p53 immunoexpression is strongly associated with high grade dysplasia and risk for malignant transformation in potentially malignant oral lesions from Northern Ireland

AIMS: No good predictive marker for the malignant transformation of potentially malignant oral lesions (PMOLs) is currently available. This study re-evaluated the value of p53 immunoexpression to predict malignant transformation of PMOLs after discounting possible confounding factors. METHODS: PMOLs from 18 patients who showed progression to carcinoma, 16 of the respective carcinomas, and PMOLs from 18 matched controls were evaluated by immunohistochemistry (IHC) for p53 expression. A mouse monoclonal antibody that detects wild-type and mutant forms of human p53 was used. The p53 immunostaining pattern was also correlated with the degree of dysplasia. RESULTS: Suprabasal p53 staining was significantly associated with high grades of dysplasia (p < 0.01). The specificity and positive predictive value (PPV) for malignant transformation of suprabasal p53 staining were superior to the assessment of dysplasia, but sensitivity was inferior. All carcinomas derived from PMOLs with suprabasal p53 showed strong p53 immunostaining. However, the absence of suprabasal p53 staining and/or dysplastic changes did not preclude malignant transformation in a considerable proportion of PMOLs. CONCLUSIONS: This study confirms and extends previous findings that suprabasal p53 immunoexpression has a high PPV for malignant transformation of PMOLs and can be used as a specific marker for lesions that are at high risk for malignant transformation. The absence of suprabasal p53 staining (that is, absence of, or basal, p53 staining) is non-informative for prognostic purposes. Because of its limited sensitivity, p53 IHC is not a substitute for the assessment of dysplasia in the evaluation of PMOLs. Instead, p53 IHC emerges as a clinically useful supplement of histopathological assessment in the prognosis of PMOLs.     

Highly Polymorphic Domains of the Human Serum Amyloid A (SAA) Gene GSAA1

The DNA of the human serum amyloid A (SAA) gene GSAA1 contains several repetitive regions within its introns. We have studied length variations at one such region in the 2nd intron by selective amplification using the polymerase chain reaction (PCR) and defined oligonucleotide primers. The lengths of the repetitive regions frequently differ between individual chromosomes and can be transmitted as Mendelian markers, making them useful for genetic linkage analysis.     

Mosaicism in amniotic fluid cell cultures: Classification and significance

The last decade has witnessed increasing application of human cytogenetic technology to prenatal chromosome analysis. However, unlike the rather uniform peripheral blood T-lymphocyte system which has provided most of our experience in human cytogenetics, long-term amniotic-fluid cell cultures display extreme cellular heterogeneity and disproportionate growth of certain cell types as a consequence of clonal amplification. When they enter cell culture, many of these cells are approching the terminal stages of their respective life spans and may have accumulated chromosomal aberrations. Concern about the possibility of true fetal mosaicism seems warranted chiefly in situations were multiple colonies display potentially viable aberrations. Clonal analysis, preferable of multiple clonal types, and attention to details of clonal morphology are likely to minimize diagnostic errors and undue apprehension resulting from mosaicism in amniotic-fluid cell cultures.