Brittle cornea syndrome associated with a missense mutation in the zinc-finger 469 gene.
OBJECTIVE
To investigate the diverse clinical manifestations, identify the causative mutation and explain the association with red hair in a family with brittle cornea syndrome (BCS).


METHODS
Eight family members in three generations underwent ophthalmic, dental, and general medical examinations, including radiologic examination of the spine. Bone mineral density (BMD) and serum levels of vitamin D, parathyroid hormone, and biochemical markers for bone turnover were measured. Skin biopsies were examined by light and transmission electron microscopy. Molecular genetic studies included homozygosity mapping with SNP markers, DNA sequencing, and MC1R genotyping.


RESULTS
At 42 and 48 years of age, respectively, both affected individuals were blind due to retinal detachment and secondary glaucoma. They had extremely thin and bulging corneas, velvety skin, chestnut colored hair, scoliosis, reduced BMD, dental anomalies, hearing loss, and minor cardiac defects. The morphologies of the skin biopsies were normal except that in some areas slightly thinner collagen fibrils were seen in one of the affected individuals. Molecular genetic analysis revealed a novel missense mutation of ZNF469, c.10016G>A, that was predicted to affect the fourth of the five zinc finger domains of ZNF469 by changing the first cysteine to a tyrosine (p.Cys3339Tyr). Both affected individuals were homozygous for the common red hair variant R151C at the MC1R locus.


CONCLUSIONS
BCS is a disorder that affects a variety of connective tissues. Reduced BMD and atypical dental crown morphology have not been reported previously. The results confirm that BCS is associated with mutations in ZNF469. The association with red hair in some individuals with BCS is likely to occur by chance.
Christensen
Anne E
AE
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
Knappskog
Per M
PM
Midtbø
Marit
M
Gjesdal
Clara G
CG
Mengel-From
Jonas
J
Morling
Niels
N
Rødahl
Eyvind
E
Boman
Helge
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density; D003316:Corneal Diseases / Q000235:genetics*; D003744:Dental Enamel Hypoplasia / Q000175:diagnosis / Q000235:genetics; D005260:Female; D005838:Genotype; D006200:Hair Color / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010281:Parathyroid Hormone / Q000097:blood; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011859:Radiography; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics; D012600:Scoliosis / Q000000981:diagnostic imaging / Q000235:genetics; D017422:Sequence Analysis, DNA; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*; D014807:Vitamin D / Q000097:blood; D055815:Young Adult
D010281:Parathyroid Hormone; D044102:Receptor, Melanocortin, Type 1; D014157:Transcription Factors; C530065:ZNF469 protein, human; D014807:Vitamin D