Wiley

In order to provide data relevant to a search for modifying genes for age of onset in Huntington disease, we examined the relationship between CAG number and age of onset in a total of 370 individuals from 165 siblingships, in two cohorts of siblings with Huntington disease: an American group of 144 individuals from 64 siblingships, and a Canadian population of 255 individuals from 113 siblingships. Using a logarithmic model to regress the age of onset on the number of CAG triplets, we found that CAG number alone accounted for 65%–71% of the variance in age of onset. The siblingship an individual belonged to accounted for 11%–19% of additional variance. This adds to the previous evidence that there are familial modifiers of the age of onset, independent of the CAG number. Such modifiers may consist of additional genes, which could be the target of a linkage study. A linkage study is feasible with the cooperation of a number of major centers and may be made more efficient by concentrating on sibling pairs that are highly discordant for age of onset. © 2001 Wiley‐Liss, Inc.

In a Portuguese‐American family with hereditary amyloid neuropathy (familial amyloidotic polyneuropathy), onset was in the seventh decade in all affected relatives. Another unusual characteristic was their origin from the Portuguese island of Madeira. In spite of this, the mutant transthyretin (TTR^Met30) (the same variant prealbumin that is the circulating precursor of AF_P protein in the classic Portuguese patients) could be found in the propositus plasma. In addition, three other asymptomatic relatives (ages 90, 73, and 48) were shown to carry the mutation.

Late onset and incomplete penetrance, at a clinical level, raise problems for presymptomatic detection of mutant TTR, as these tend to cluster in families. When counseling asymptomatic heterozygotes, we must consider intra‐familial correlation in age‐of‐onset, and the distribution of age‐of‐onset including age of unaffected heterozygotes.

This family poses interesting questions regarding pathogenesis of this degenerative process and the influence of other genetic factors, such as modifiers, epistasis, and polymorphism of the TTR genes or their regulators. A cis‐effect of a gene linked to the mutant gene, decreasing the synthesis of the mutant TTR and keeping a sufficient amount of the normal one in circulation, or producing some cofactor for TTR, could also explain late onset and apparently incomplete penetrance; the occasional finding of classic forms in these families would be the result of recombinatory events.

Cryptic subtelomeric chromosome anomalies have been recognized as a significant cause of dysmorphology and mental retardation. To determine whether the clinical cytogenetics laboratory should screen routinely for these aberrations, we have tested 250 patients with idiopathic mental retardation/developmental delay, either isolated (53) or associated with dysmorphic features and/or malformations in the absence of a recognizable syndrome (197). All had normal karyotypes at the 550–850 band level. Subtelomeric anomalies were found in 1/53 of the first group (1.9%) and 8/197 of the second group (4.1%). In one patient, two separate anomalies were present: a deletion (not inherited) and a duplication (inherited). It is possible that one of these 10 observed aberrations might represent a rare and previously unreported polymorphism and one a rare cross‐hybridization. Our study supports the proposition that cryptic subtelomeric rearrangements are a significant cause of idiopathic mental retardation/developmental delay, but both the diversity of the phenotypes of the positive cases and the wide diversity of their associated chromosome abnormalities emphasize the central problem for the clinical cytogenetics laboratory—that of choosing the most productive patient base for this useful diagnostic test. © 2002 Wiley‐Liss, Inc.

In a series of 25 Japanese patients with Rubinstein‐Taybi syndrome, we screened, by high‐resolution GTG banding and fluorescence in situ hybridization of a cosmid probe (RT1, D16S237), for microdeletions associated with this syndrome. In one patient, a microdeletion was demonstrated by in situ hybridization, but none were detected by high‐resolution banding. © 1994 Wiley‐Liss, Inc.

To identify genes responsible for the susceptibility for schizophrenia, and to test the hypothesis that schizophrenia is etiologically heterogeneous, we have studied 39 multiplex families from a systematic sample of schizophrenic patients. Using a complex autosomal dominant model, which considers only those with a diagnosis of schizophrenia or schizoaffective disorder as affected, a random search of the genome for detection of linkage was undertaken. Pairwise linkage analyses suggest a potential linkage (LRH = 34.7 or maximum lod score = 1.54) for one region (22q12‐q13.1). Reanalyses, varying parameters in the dominant model, maximized the LRH at 660.7 (maximum lod score 2.82). This finding is of sufficient interest to warrant further investigation through collaborative studies. © 1994 Wiley‐Liss, Inc.

Complete or incomplete androgen insensitivity (AI) not associated with deficient specific 5α‐dihydrotestosterone (DHT)‐receptor activity in cultured genital skin fibroblasts may result from a qualitative receptor abnormality or a postreceptor defect in target cell sensitivity to DHT. We have studied a sporadic patient with complete AI whose mean receptor capacity (B_max) is 34 fmol/mg protein and a second with incomplete AI, multiple affected maternal relatives, and a mean B_max of 40 (normal: 15 – 50). Each has normal 5α‐reductase activity. The following qualities of the receptor activity are normal in each: Equilibrium dissociation constant (K_d), elution profile on gel chromatography, nuclear translocation of the DHT‐receptor complex, and 0.4 M KCl extractability of the nuclear complex. When preincubated at 37°C and assayed at 42°C (compared with the usual 37°C) the receptor activity in cells of the “complete AI” patient decreased much more (60%) than that of any of 7 control cell lines (± 20%); the activity in cells of the “incomplete AI” patient, in contrast, decreased to a variable, questionably abnormal extent. When preincubated, assayed, and chased at 37°C with excess radioinert DHT, the androgen‐receptor complexes in both patients dissociated with a rate constant (k₋₁) about 18 × 10⁻³ min⁻¹ compared with a normal of 5.9 ± 0.32 × 10⁻³ min⁻¹ (± SEM; n = 15). We have thus defined novel qualitative defects of the androgen receptor activity in two patients who have different clinical degrees of congenital AI despite normal levels of androgen binding. These defects will be useful as markers for genetic studies and as molecular models for steroid‐resistant cancer in man.

The identification of the factors which regulate the proliferation and differentiation of cells of the osteoblast lineage remains one of the major challenges in the field of bone cell biology. Although considerable progress has been made in the isolation and culture of cells of the osteoblast lineage from both animal and, more recently, human bone, uncertainties have persisted as to the extent to which these cell populations retain the ability to differentiate into functional osteoblasts in vitro.

The formation in vitro of mineralized nodules that exhibit the morphological, ultrastructural and biochemical characteristics of embryonic/woven bone formed in vivo, represents the first evidence that the differentiation of functional osteoblasts can occur in cultures of isolated animal bone‐derived cell populations. It is clear, however, that the culture conditions employed at present only permit a small number of cells to differentiate to the extent of being capable of organising their extracellular matrix into a structure that resembles that of bone. Moreover, it has generally been found that the reproducible mineralization of this extracellular matrix requires supplementation of the culture medium with mM concentrations of β‐GP, which raises doubts as to the physiological relevance of this process.

The formation of nodules has also been observed in cultures of human bone‐derived cells. As found in cultures of animal bonederived cells, reproducible mineralization of these nodules will occur in the presence of β‐GP. We have shown, however, that in the presence of the long acting ascorbate analogue Asc‐2‐P, the formation and mineralization of nodules can occur in the absence of β‐GP. The nodules formed in human bone‐derived cell cultures have yet to be characterized as rigorously as those formed in cultures of animal bone‐derived cells and thus it remains to be shown that they resemble bone formed in vivo.

Two widely used affected‐sib‐pair scoring procedures (the Green and Woodrow [1977] procedure, and the method of forming all possible affected‐sib‐pairs) are compared with a new method for their relative efficiency in detecting the presence of an HLA‐linked disease susceptibility gene. Their relative performance is investigated by extensive computer simulations over a large number of disease transmission models. On the average, the new procedure appears to outperform the Green and Woodrow method and the “all‐possible‐pairs” method.

From a series of 1265 individuals with different craniosynostoses hospitalized between 1976 and 1993, 260 probands with nonsyndromic unilateral (181) or bilateral (79) coronal synostosis were analysed. The prevalence of craniosynostoses was estimated as 1 in 2100 children. In the group of coronal synostosis, family history was obtained on 192 probands in 180 pedigrees. The male:female ratio was 1:2. The average paternal age was 32.7 ± 6.4 years, which is significantly higher than normal. In 26 of the 180 pedigrees, a high degree of familial aggregation was observed, giving a 14.4% figure of familial cases. The bicoronal synostoses were significantly more often familial than the unicoronal synostoses. Segregation analysis of these families leads to the conclusion that coronal synostosis is transmitted as a dominant disorder with 0.60 penetrance and 61% of sporadic cases. © 1995 Wiley‐Liss, Inc.