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A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance.

ABSTRACT: We previously reported the existence of a unique autosomal recessive syndrome consisting of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance mapping to chromosome 15q26.In this manuscript, we have used whole exome sequencing on two affected members of a consanguineous family with this condition and carried out detailed bioinformatics analysis to elucidate the causative mutation.Our analysis resulted in the identification of a homozygous p.N1060S missense mutation in a highly conserved residue in KIF7, a regulator of Hedgehog signaling that has been recently found to be causing Joubert syndrome, fetal hydrolethalus and acrocallosal syndromes. The phenotype in our patients partially overlaps with the phenotypes associated with those syndromes but they also exhibit some distinctive features including multiple epiphyseal dysplasia.We report the first missense homozygous disease-causing mutation in KIF7 and expand the clinical spectrum associated with mutations in this gene to include multiple epiphyseal dysplasia. The missense nature of the mutation might account for the unique presentation in our patients.

SUBMITTER: Ali BR

PROVIDER: S-EPMC3492204 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance.

Ali Bassam R BR Silhavy Jennifer L JL Akawi Nadia A NA Gleeson Joseph G JG Al-Gazali Lihadh L

Orphanet journal of rare diseases 20120515

<h4>Background</h4>We previously reported the existence of a unique autosomal recessive syndrome consisting of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance mapping to chromosome 15q26.<h4>Methods</h4>In this manuscript, we have used whole exome sequencing on two affected members of a consanguineous family with this condition and carried out detailed bioinformatics analysis to elucidate the causative mutation.<h4>Results</h4>Our analysis resulted in the identifica ...[more]

PMID: 22587682

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Project description:PurposeTo identify the molecular basis of non-syndromic autosomal recessive congenital cataracts (arCC) in a consanguineous family.MethodsAll family members participating in the study received a comprehensive ophthalmic examination to determine their ocular phenotype and contributed a blood sample, from which genomic DNA was extracted. Available medical records and interviews with the family were used to compile the medical history of the family. The symptomatic history of the individuals exhibiting cataracts was confirmed by slit-lamp biomicroscopy. A genome-wide linkage analysis was performed to localize the disease interval. The candidate gene, LIM2 (lens intrinsic membrane protein 2), was sequenced bi-directionally to identify the disease-causing mutation. The physical changes caused by the mutation were analyzed in silico through homology modeling, mutation and bioinformatic algorithms, and evolutionary conservation databases. The physiological importance of LIM2 to ocular development was assessed in vivo by real-time expression analysis of Lim2 in a mouse model.ResultsOphthalmic examination confirmed the diagnosis of nuclear cataracts in the affected members of the family; the inheritance pattern and cataract development in early infancy indicated arCC. Genome-wide linkage analysis localized the critical interval to chromosome 19q with a two-point logarithm of odds (LOD) score of 3.25. Bidirectional sequencing identified a novel missense mutation, c.233G>A (p.G78D) in LIM2. This mutation segregated with the disease phenotype and was absent in 192 ethnically matched control chromosomes. In silico analysis predicted lower hydropathicity and hydrophobicity but higher polarity of the mutant LIM2-encoded protein (MP19) compared to the wild-type. Moreover, these analyses predicted that the mutation would disrupt the secondary structure of a transmembrane domain of MP19. The expression of Lim2, which was detected in the mouse lens as early as embryonic day 15 (E15) increased after birth to a level that was sustained through the postnatal time points.ConclusionA novel missense mutation in LIM2 is responsible for autosomal recessive congenital cataracts.

Dataset Information

A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance.

Publications

A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance.

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