Mutation analysis of Jewish hunter patients in Israel

We have performed molecular and mutation analyses on 14 unrelated Israeli Hunter families and have identified the IDS mutation in 8 of them. Three unrelated Ashkenazi patients had the same previously reported mutation (1246 C→T). Based on the haplotypes of the mutation-bearing chromosomes, we concluded that this is a recurrent mutation. In two patients, we identified a deletion spanning exons V–VII. Three novel mutations were observed in different patients: L410P, 717del4, and 244del3. In addition, the silent mutation (562 C→T) was observed in one patient. © 1994 Wiley-Liss, Inc.     

The branchio-oto-renal (BOR) syndrome: report of bilateral renal agenesis in three sibs

We report a man who had the branchio-oto-renal (BOR) syndrome with crossed renal ectopia. His three children were born with bilateral renal agenesis and the so-called Potter syndrome. This case illustrates the potential severity of the renal anomalies in the BOR syndrome and the inadequacy of oligohydramnios and maternal serum alpha-fetoprotein as screening methods for renal agenesis. This case also implies strongly the necessity for meticulous search for renal anomalies in individuals with the BOR syndrome and proper counseling regarding the possibility of lethal bilateral renal agenesis.     

X inactivation phenotype in carriers of Pelizaeus-Merzbacher disease: skewed in carriers of a duplication and random in carriers of point mutations

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disease caused by coding sequence mutations in the PLP gene, sub-microscopic duplications of variable sizes including the PLP gene or very rarely deletions of the PLP gene. We analysed the X inactivation pattern in blood of PMD female carriers with duplications and with point mutations. In the majority of duplication carriers (7/11), the X chromosome bearing the duplication was preferentially inactivated, whereas a random pattern of X inactivation was detected in point mutation carriers (3/3), a deletion carrier (1/1), affected females (4/4) who did not have a recognised mutation and normal control females. However 2/5 non-carrier female relatives of patients with a duplication, had skewed X inactivation. The skewed pattern of inactivation observed in most duplication carriers and not in mutation carriers suggests a) that there is selection against those cells in which the duplicated X chromosome is active and b) other expressed sequences within the duplicated region rather than mutant PLP may be responsible. Since the skewed X inactivation did not segregate with the disease in two families and the pattern of X inactivation was variable among the duplication carriers, the pattern X inactivation is an unsuitable diagnostic tool for female carriers of PMD.     

A large deletion mutation in the CFTR gene (3120+1Kbdel8.6Kb): a founder mutation in the Palestinian Arabs. Mutation in brief no. 231. Online

A deletion mutation of 8.6Kb in the CFTR gene, spanning the exons 17a, 17b and 18 was identified in 4 homozygous unrelated Palestinian CF patients. The patients were of various ethnic subgroups including Muslims, Christians and Druze. The deletion breakpoint occurred within an identical 4bp sequence in introns 16 and 18, and the mutation was defined as 3120+1Kbdel8.6Kb. A simple PCR based assay was designed and using this assay two compound heterozygote patients with the 3120+1Kbdel8.6Kb were identified. The 3120+1Kbdel8.6Kh hearing chromosomes had a common intragenic haplotype and variable flanking polymorphic markers, indicating that it is an ancient founder mutation.     

Duplication of distal 22q

We report on three patients with duplication of distal 22q. One patient is a de novo carrier of the translocation t(21;22) (p13;q11), the other two are offspring of a translocation carrier t(10;22) (q26;q12). The clinical manifestations of these patients demonstrate the variability of the dup(22q) syndrome.     

A de novo translocation, 14q21q,with a microchromosome—14p21p

A familial translocation, t(14;21)(14p21p;14q21q), in a mother and her child is described. The translocation was ascertained through the birth of a Down syndrome baby with the chromosome constitution 47,XX,-14, +der 14, +der 21,t(14;21)(q11; p12) mat. A 1:3 segregation in the maternal meiosis is suggested for the evolution of the unbalanced chromosome state. The main translocated chromosome 14q21q mimics the product of a Robertsonian translocation, while the 14p21p chromosome has the morphology of a satellited microchromosome. The cytogenetic nature of this translocation is discussed.     

Mutant mice lacking the gamma isoform of protein kinase C show decreased behavioral actions of ethanol and altered function of gamma-aminobutyrate type A receptors.

Calcium/phospholipid-dependent protein kinase (protein kinase C, PKC) has been suggested to play a role in the sensitivity of gamma-aminobutyrate type A (GABAA) receptors to ethanol. We tested a line of null mutant mice that lacks the gamma isoform of PKC (PKC gamma) to determine the role of this brain-specific isoenzyme in ethanol sensitivity. We found that the mutation reduced the amount of PKC gamma immunoreactivity in cerebellum to undetectable levels without altering the levels of the alpha, beta I, or beta II isoforms of PKC. The mutant mice display reduced sensitivity to the effects of ethanol on loss of righting reflex and hypothermia but show normal responses to flunitrazepam or pentobarbital. Likewise, GABAA receptor function of isolated brain membranes showed that the mutation abolished the action of ethanol but did not alter actions of flunitrazepam or pentobarbital. These studies show the unique interactions of ethanol with GABAA receptors and suggest protein kinase isoenzymes as possible determinants of genetic differences in response to ethanol.     

Addenda

We describe a female infant with manifestations of complete monosomy for chromosome 21 intrauterine growth retardation, failure to thrive, craniofacial anomalies, arthrogryposis-like features, and psychomotor retardation. Chromosome analysis demonstrated mosaicism for three different cell lines in the various tissues examined; 45,XX,–21/46,XX,del(21)(q11) 46,XX. The existence of these three lines suggests a possible explanation for the few cases of “complete monosomy 21” which have been reported.     

Comparison of sucking patterns at introduction of oral feeding and at term in Israeli and American preterm infants

BACKGROUND: It has been hypothesized that early initiation of oral feeding in premature infants may enhance the maturation of sucking patterns. AIM: To compare preterm infant sucking characteristics in urban level III neonatal care units in the USA and Israel. The two hospitals have different practices regarding the introduction of oral feeding. METHODS: Infants were assessed at 34-35 wk postconceptional age (PCA) and at term. Sucking parameters were assessed with the Kron's Nutritive Sucking Apparatus. RESULTS: 70 infants (38 Americans and 32 Israelis) participated in the study. Oral feedings were initiated earlier (32.6 +/- 4.3 vs 34.5 +/- 1.8 wk PCA, p < 0.01) and full oral feedings were reached earlier (35.4 +/- 2.8 vs 36.5 +/- 2.5 wk PCA, p < 0.05) in the USA infants. American preterm infants produced significantly more sucks (p < 0.001), had a higher suck rate (p < 0.001), more sucks per burst (p < 0.05), and a shorter interburst width (p < 0.01) at 34 wk PCA than Israeli infants. At term, American infants produced significant more sucks (p < 0.001), higher suck rate (p < 0.001), shorter intersuck width (p < 0.001), and a shorter interburst width (p < 0.05) than the Israeli infants of the same PCA. CONCLUSION: Different practices in the care of preterm infants, such as postconceptional age at introduction of oral feeding, may play a role in the development of feeding and feeding organization at term.     

The R245X mutation of PCDH15 in Ashkenazi Jewish children diagnosed with nonsyndromic hearing loss foreshadows retinitis pigmentosa

Usher syndrome is a frequent cause of the combination of deafness and blindness due to retinitis pigmentosa (RP). Five genes are known to underlie different forms of Usher syndrome type I (USH1). In the Ashkenazi Jewish population, the R245X mutation of the PCDH15 gene may be the most common cause of USH1 (Ben-Yosef T, Ness SL, Madeo AC, Bar-Lev A, Wolfman JH, Ahmed ZM, Desnick RK, Willner JP, Avraham KB, Ostrer H, Oddoux C, Griffith AJ, Friedman TB N Engl J Med 348: 1664-1670, 2003). To estimate what percentage of Ashkenazi Jewish children born with profound hearing loss will develop RP due to R245X, we examined the prevalence of the R245X PCDH15 mutation and its carrier rate among Ashkenazi Jews in Israel. Among probands diagnosed with nonsyndromic hearing loss not due to mutations of connexin 26 (GJB2) and/or connexin 30 (GJB6), and below the age of 10, 2 of 20 (10%) were homozygous for the R245X mutation. Among older nonsyndromic deaf individuals, no homozygotes were detected, although one individual was heterozygous for R245X. The carrier rate of the R245X mutation among the normal hearing Ashkenazi population in Israel was estimated at 1%. Ashkenazi Jewish children with profound prelingual hearing loss should be evaluated for the R245X PCDH15 mutation and undergo ophthalmologic evaluation to determine whether they will develop RP. Rehabilitation can then begin before loss of vision. Early use of cochlear implants in such cases may rescue these individuals from a dual neurosensory deficit.