V M Der Kaloustian

Silencing of CDKN1C (p57KIP2) is associated with hypomethylation at KvDMR1 in Beckwith–Wiedemann syndrome

Context: Beckwith–Wiedemann syndrome (BWS) arises by several genetic and epigenetic mechanisms affecting the balance of imprinted gene expression in chromosome 11p15.5. The most frequent alteration associated with BWS is the absence of methylation at the maternal allele of KvDMR1, an intronic CpG island within the KCNQ1 gene. Targeted deletion of KvDMR1 suggests that this locus is an imprinting control region (ICR) that regulates multiple genes in 11p15.5. Cell culture based enhancer blocking assays indicate that KvDMR1 may function as a methylation modulated chromatin insulator and/or silencer. Objective: To determine the potential consequence of loss of methylation (LOM) at KvDMR1 in the development of BWS. Methods: The steady state levels of CDKN1C gene expression in fibroblast cells from normal individuals, and from persons with BWS who have LOM at KvDMR1, was determined by both real time quantitative polymerase chain reaction (qPCR) and ribonuclease protection assay (RPA). Methylation of the CDKN1C promoter region was assessed by Southern hybridisation using a methylation sensitive restriction endonuclease. Results: Both qPCR and RPA clearly demonstrated a marked decrease (86–93%) in the expression level of the CDKN1C gene in cells derived from patients with BWS, who had LOM at KvDMR1. Southern analysis indicated that downregulation of CDKN1C in these patients was not associated with hypermethylation at the presumptive CDKN1C promoter. Conclusions: An epimutation at KvDMR1, the absence of maternal methylation, causes the aberrant silencing of CDKN1C, some 180 kb away on the maternal chromosome. Similar to mutations at this locus, this silencing may give rise to BWS.

The myopathology of the Prune belly syndrome.

Abstract The Prune Belly Syndrome or Triad Syndrome is a rare disorder characterized by hypoplasia or aplasia of abdominal musculature, urogenital anomalies and undescended testicles. The majority of the reported cases are males. A female case of the mild variant of this syndrome is presented. The light and electron microscopic changes in the voluntary muscles are described. They consisted of variations in fibre size, fibre necrosis, an increase in sarcolemmal nuclei, the presence of capillaries within muscle fibres, excessive collagen accumulation, Z-line abnormalities, sarcoplasmic reticulum dilatation and myofilamentous disarray and loss. We propose the hypothesis that a genetically-determined or congenital type of myopathy may be the basis of this syndrome.

Hereditary retinoblastoma and 13q--mosaicism.

Mosaicism for a 13q interstitial deletion was found in a minor fraction of peripheral blood lymphocytes in a 10-month-old girl affected with bilateral retinoblastoma. The tumor was inherited from the unilaterally affected father.

Concentrically laminated membranous inclusions in myofibres of Dyggve-Melchior-Clausen syndrome

Abstract Concentrically-laminated membranous inclusions reported only once previously, are described in muscle from a patient with the Dyggve-Melchior-Clausen syndrome. They exhibit a banding pattern and are characteristically located in subsarcolemmal sites. They may represent a non-specific myopathological reaction.

Familial imperforate anus: Report of a family.

SummaryA family with three female siblings affected with imperforate anus and rectovaginal fistula is reported. This is the twelfth family in the literature with more than one member born with imperforate anus. A multifactorial genetic etiology of this condition is suggested.

Evidence for a fourth locus in Usher syndrome type I.

Usher syndrome type I (US1) is an autosomal recessive condition in which three different genes have been already localised (USH1A, USH1B, and USH1C on chromosomes 14q32, 11q13, and 11p15 respectively). The genetic heterogeneity of US1 has been confirmed in a previous study by linkage analysis of 20 French pedigrees. Here, we report the genetic exclusion of the three previously reported loci in two large multiplex families of Moroccan and Pakistani origin, suggesting the existence of at least a fourth locus in Usher syndrome type I.

The autosomal recessive variety of congenital stationary night-blindness with myopia.

Congenital stationary night-blindness associated with myopia may be transmitted by two types of inheritance: X-linked recessive (Worth, 1906; Nettleship, 1909 and 1912; Kleiner, 1923) and autosomal recessive (Nettleship, 1912; Vogt, 1923; Gassler, 1925; Akiya, 1935; Merin et al, 1970). There are only a few reports of either variety. The present paper describes a family where 3 sibs are affected with the autosomal recessive form of congenital night-blindness with myopia. To our knowledge this is the third report of this condition in the English literature.

Psychosocial and economic profile of a sample of families with thalassaemic children in Lebanon.

Thalassaemia major is a relatively common disease in Lebanon. This study of 41 families with 54 patients attending the American University of Beirut Medical Center was conducted to define some aspects of the disease in Lebanon and to assess the attitudes of affected families on relevant psychosocial and economic issues. We conclude that because of the high frequency of consanguineous marriage, thalassaemia major is more common in Lebanon than might be expected on the basis of the incidence of the trait. Most patients are diagnosed early in life, but their treatment is generally far from adequate; securing desferrioxamine and paying for follow up visits to the doctor seem to be the most important financial burdens. The general population of the country is not properly informed yet and about 70% of the families had not heard about the disease before having an affected child. The inherited nature of the disease is not clear in the minds of a high percentage of the families, and in about 30% of cases the family had not been told about the advisability of screening to detect heterozygotes. The great majority of families favour a preventive approach to thalassaemia, based on heterozygote screening and the possibility of prenatal diagnosis.

Translocation between chromosomes 6 and 15 (45,XX,t(6;15)(q25;q11.2)) with further evidence for lack of imprinting of the insulin-like growth factor II/mannose-6-phosphate receptor in humans.

We report a 24 year old female with growth retardation, microcephaly, and congenital abnormalities who has an unbalanced de novo translocation between chromosomes 16 and 6: 45,XX,t(6;15)(q25;q11.2). FISH analysis confirmed that the deletion on chromosome 15 is proximal to the Prader-Willi locus. Several genes have been assigned to the 6q25-qter region including the insulin-like growth factor II/mannose-6-phosphate (IGF-II/M6P) receptor. DNA analysis from our patient documented the loss of one IGF2R gene copy. These data confirm the localisation of the IGF2R receptor to distal 6q25. We also showed reduced expression of the soluble and membrane bound IGF-II receptor, a gene dosage effect incompatible with imprinting. The IGF2R gene has been shown to be imprinted in the mouse but not in humans. Our data provide further evidence for lack of imprinting of this gene in humans.

Atypical serum cholinesterase in a family with congenital distichiasis.

This paper describes the coexistence of genetically determined reduced cholinesterase activity and congenital distichiasis in the same family. The pedigree suggests that these two autosomal dominant diseases are segregated independently and do not show evidence of linkage.