Juvenile bilateral lens dislocation and glaucoma associated with a novel mutation in the fibrillin 1 gene.
OBJECTIVE
To describe the clinical, ocular, and genetic findings in multiple members of a family with early-onset and bilateral lens dislocation, clinical corneal guttae, and glaucoma.


METHODS
All family members underwent complete physical and ophthalmic examinations. After informed consent was given, DNA was obtained from eleven family members, eight of whom were affected. Three polymorphic markers near the fibrillin 1 (FBN1) locus were genotyped and the results analyzed using the VITESSE program. Amplification of the 65 exons and flanking intronic sequences of FBN1 was performed using polymerase chain reaction (PCR), followed by conformation sensitive gel electrophoresis (CSGE). Then, all fragments with mobility variations were sequenced.


RESULTS
Pedigree analysis revealed a three generation family with eight of eleven individuals affected by early onset lens dislocation, high myopia, typical facies, frontal bossing, flexion contractures, proximal interphalangeal (PIP) joint thickening, clinical corneal guttae, and glaucoma. Genetic linkage analysis using polymorphic markers near FBN1 demonstrated an LOD score of 1.78 (maximum possible LOD score 1.78). Conformation sequence gel electrophoresis analysis suggested a sequence variation in exon 3. Sequencing revealed a C965G substitution, resulting in an S322C coding change. This sequence variant segregated with affection status and was not identified in 154 control chromosomes.


CONCLUSIONS
This syndrome is consistent with a novel mutation in the FBN1 gene. FBN1 mutations have been previously described as causative for Marfan syndrome. The early-onset of complete lens dislocation, progressive corneal guttae, and glaucoma is unusual for Marfan syndrome. This study expands the Marfan phenotype and demonstrates a possible link between guttae, glaucoma, and fibrillin 1 disorders.
Challa
Pratap
P
Department of Ophthalmology, Duke University Medical Center, Durham, NC 27710, USA. Chall001@mc.duke.edu
Hauser
Michael Arthur
MA
Luna
Coralia Catalina
CC
Freedman
Sharon Fridovich
SF
Pericak-Vance
Margaret
M
Yang
Jun
J
McDonald
Marie Theresa
MT
Allingham
R Rand
RR
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D003316:Corneal Diseases / Q000235:genetics; D003545:Cysteine; D005091:Exons; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D008040:Genetic Linkage; D005901:Glaucoma / Q000235:genetics*; D006801:Humans; D007906:Lens Subluxation / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D012694:Serine; D013577:Syndrome; D054392:Adipokines
D003545:Cysteine; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D012694:Serine; C000605722:FBN1 protein, human; D054392:Adipokines