Dataset Information

A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy.

ABSTRACT: Inositol polyphosphate-5-phosphatase K [INPP5K (MIM: 607875)] acts as a PIP3 5-phosphatase and regulates actin cytoskeleton, insulin, and cell migration. Biallelic pathogenic variants in INPP5K have recently been reported in patients affected by a form of muscular dystrophy with childhood onset. Affected patients have limb girdle muscle weakness, often associated with bilateral cataracts, short stature, and intellectual disability. Here we report four patients affected by INPP5K-related muscle dystrophy, who were apparently unrelated but originated from the same geographical area in South Italy. These patients manifest a recognizable phenotype characterized by early onset muscular dystrophy associated with short stature and intellectual disability. All affected subjects were homozygous or compound heterozygous for the c.67G > A (p.Val23Met) missense change and shared a common haplotype, indicating the occurrence of a founder effect.

SUBMITTER: D'Amico A

PROVIDER: S-EPMC7530278 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy.

D'Amico Adele A Fattori Fabiana F Nicita Francesco F Barresi Sabina S Tasca Giorgio G Verardo Margherita M Pizzi Simone S Moroni Isabella I De Mitri Francesca F Frongia Annalia A Pane Marika M Mercuri Eugenio E Tartaglia Marco M Bertini Enrico E

Frontiers in genetics 20200918

Inositol polyphosphate-5-phosphatase K [INPP5K (MIM: 607875)] acts as a PIP3 5-phosphatase and regulates actin cytoskeleton, insulin, and cell migration. Biallelic pathogenic variants in INPP5K have recently been reported in patients affected by a form of muscular dystrophy with childhood onset. Affected patients have limb girdle muscle weakness, often associated with bilateral cataracts, short stature, and intellectual disability. Here we report four patients affected b ...[more]

PMID: 33193651

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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 Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy.

Publications

A Recurrent Pathogenic Variant of <i>INPP5K</i> Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy.

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