Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3).

PURPOSE: Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS: All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS: Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G-->A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C-->T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A. CONCLUSIONS: The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype.

A novel dysmorphic syndrome with open calvarial sutures and sutural cataracts maps to chromosome 14q13-q21.

We describe a new dysmorphic syndrome in an inbred Saudi Arabian family with 21 members. Five males and one female have similar craniofacial features including wide open calvarial sutures with large and late-closing anterior fontanels, frontal bossing, hyperpigmentation with capillary hemangioma of the forehead, significant hypertelorism, and a broad and prominent nose. In addition, these individuals have Y-shaped sutural cataracts diagnosed by 1-2 years of age. No chromosomal or biochemical abnormalities were identified. A genome-wide scan was performed, and two-point LOD score analysis, assuming autosomal recessive inheritance, detected linkage to chromosome 14q13-q21. The highest LOD scores were obtained for marker GATA136A04 (LOD=4.58 at theta=0.00) and for the adjacent telomeric marker D14S1048 (LOD=4.32 at theta=0.00). Multipoint linkage analysis resulted in a maximum LOD score of 5.44 between markers D14S1048 and GATA136A04. Model independent analysis by SIBPAL confirmed linkage to the same chromosomal region. Haplotype analysis indicated that all affected individuals were homozygous for the interval on chromosome 14q13-q21 with two recombinants for D14S1014 (centromeric) and one recombinant for D14S301 (telomeric). These recombinations limit the disease locus to a region of approximately 7.26 Mb. Candidate genes localized to this region were identified, and analysis of PAX9 did not identify mutations in these patients. The unique clinical phenotype and the mapping data suggest that this family represents a novel autosomal recessive syndrome.

Mitotic activity in the lens rudiment of the chicken embryo before and after the onset of crystallin synthesis : II. Immunofluorescence studies.

1. The fluorescent antibody method was used to study the first appearance of delta-crystallin in the lens rudiment of the chicken embryo, in relation to the cell cycle. At the beginning of lens invagination a few cells, with their nuclei in a basal position, displayed fluorescence. The percentage of cells with a positive reaction increased steadily, but it was not until invagination was well underway, about 3 hours after its start, that fluorescence was seen in dividing cells. It was concluded that in this system cell replication and synthesis of specific protein are not mutually exclusive. 2. Because the number of hours passing by before the appearance of fluorescent mitoses was about equal to the previously calculated duration of the G-2 phase of the cell cycle it follows that crystallin production becomes detectable in the late S- or early G-2 phase. Observations on the cellular shape, which is a function of cell cycle phase, at the time that cells first reacted with the fluorescent antibodies agree with this interpretation. 3. The suggestion is made that the inductive influence of the optic cup on the lens primordium may primarily be exerted during the DNA synthetic phase of the presumptive lens cells.

Mitotic activity in the lens rudiment of the chicken embryo before and after the onset of crystallin synthesis : I. Results of treatment with Colcemid.

1. Previous work has shown that the lens rudiment of the chicken embryo starts producing crystallins in stage 14 at the beginning of invagination (Ikeda and Zwaan, 1966). To establish if this appearance of organ-specific proteins is coupled with changes in cell replication, the mitotic activity in the anlage was determined by Colcemid treatment in stages 10 to 17. No significant differences in activity were noted between the center and the periphery of the organ in the stages studied or between stages of development. 2. We conclude that cessation of cell replication and the onset of crystallin production are not directly linked. 3. A mitotic duration of 24 min and a total cell cycle time of 15 h were calculated. The latter value does not agree with data from earlier studies using autoradiography after3H-thymidine application. Possible reasons for the discrepancy are discussed and caution is urged in the interpretation of cell cycle data obtained by treatment with mitotic inhibitors.