Manifestations in four males with and an obligate carrier of the Lenz microphthalmia syndrome

Forrester, Shawnia; Kovach, Margaret J.; Reynolds, N.M.; Urban, Robert C.; Kimonis, Virginia

doi:10.1002/1096-8628(20010101)98:1<92::aid-ajmg1009>3.0.co;2-o

Cited by 34 publications

(37 citation statements)

References 12 publications

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“…Clinical features of the family discussed in this study have been previously reported 4. Briefly, three brothers and a maternal uncle had congenital anophthalmia, delayed motor development, hypotonia, and mental retardation 4. They also have abnormal ears, high-arched palate, pectus excavatum, finger and toe syndactyly, clinodactyly, fetal pads, scoliosis, and cardiac and renal abnormalities 4.…”

Section: Methodsmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 95%

“…Briefly, three brothers and a maternal uncle had congenital anophthalmia, delayed motor development, hypotonia, and mental retardation 4. They also have abnormal ears, high-arched palate, pectus excavatum, finger and toe syndactyly, clinodactyly, fetal pads, scoliosis, and cardiac and renal abnormalities 4. An obligate carrier has abnormal ears and syndactyly of the second to third toes bilaterally,4 probably due to the presence of X chromosome skewing.…”

Section: Methodsmentioning

confidence: 99%

“…At least two disease loci have been described. The microphthalmia syndromic 1 locus (MCOPS1; OMIM 309800) was mapped in 1991 and again in 2001 to Xq27-q28,3 4 while the gene for the microphthalmia syndromic 2 locus (MCOPS2; OMIM 300166) showed linkage to Xp11.4–p21.2 in 2002 5 6. MCOPS1 has remained elusive since its initial mapping to Xq27-q28 more than 20 years ago.…”

Section: Introductionmentioning

confidence: 99%

“…MCOPS1 has remained elusive since its initial mapping to Xq27-q28 more than 20 years ago. Using exome sequencing of three brothers with LMS we have re-evaluated this previously characterised family4 and now identify a mutation in the NAA10 gene as a disease-causing locus for MCOPS1.…”

Section: Introductionmentioning

confidence: 99%

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A splice donor mutation inNAA10results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome

et al. 2014

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Introduction Lenz microphthalmia syndrome (LMS) is a genetically heterogeneous X-linked disorder characterised by microphthalmia/anophthalmia, skeletal abnormalities, genitourinary malformations, and anomalies of the digits, ears, and teeth. Intellectual disability and seizure disorders are seen in about 60% of affected males. To date, no gene has been identified for LMS in the microphthalmia syndrome 1 locus (MCOPS1). In this study, we aim to find the disease-causing gene for this condition. Methods and results Using exome sequencing in a family with three affected brothers, we identified a mutation in the intron 7 splice donor site (c.471+2T→A) of the N-acetyltransferase NAA10 gene. NAA10 has been previously shown to be mutated in patients with Ogden syndrome, which is clinically distinct from LMS. Linkage studies for this family mapped the disease locus to Xq27-Xq28, which was consistent with the locus of NAA10. The mutation co-segregated with the phenotype and cDNA analysis showed aberrant transcripts. Patient fibroblasts lacked expression of full length NAA10 protein and displayed cell proliferation defects. Expression array studies showed significant dysregulation of genes associated with genetic forms of anophthalmia such as BMP4, STRA6, and downstream targets of BCOR and the canonical WNT pathway. In particular, STRA6 is a retinol binding protein receptor that mediates cellular uptake of retinol/vitamin A and plays a major role in regulating the retinoic acid signalling pathway. A retinol uptake assay showed that retinol uptake was decreased in patient cells. Conclusions We conclude that the NAA10 mutation is the cause of LMS in this family, likely through the dysregulation of the retinoic acid signalling pathway.

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Section: Methodsmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A splice donor mutation inNAA10results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome

et al. 2014

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Identification of anHMGB3Frameshift Mutation in a Family With an X-linked Colobomatous Microphthalmia Syndrome Using Whole-Genome and X-Exome Sequencing

et al. 2014

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IMPORTANCE Microphthalmias are rare disorders whose genetic bases are not fully understood. HMGB3 is a new candidate gene for X-linked forms of this disease. OBJECTIVE To identify the causative gene in a pedigree with an X-linked colobomatous microphthalmos phenotype. DESIGN, SETTING, AND PARTICIPANTS Whole-genome sequencing and chromosome X-exome-targeted sequencing were performed at the High Throughput Sequencing Laboratory of the Genetic Resources Core Facility at the Johns Hopkins University School of Medicine on the DNA of the male proband and informatically filtered to identify rare variants. Polymerase chain reaction and Sanger sequencing were used to confirm the variant in the proband and the carrier status of his mother. Thirteen unrelated male patients with a similar phenotype were also screened. MAIN OUTCOMES AND MEASURES Whole-genome and X-exome sequencing to identify a frameshift variant in HMGB3. RESULTS A 2-base pair frameshift insertion (c.477_478insTA, coding for p.Lys161Ilefs*54) in the HGMB3 gene was found in the proband and his carrier mother but not in the unrelated patients. The mutation, confirmed by 3 orthogonal methods, alters an evolutionarily conserved region of the HMGB3 protein from a negatively charged polyglutamic acid tract to a positively charged arginine-rich motif that is likely to interfere with normal protein function. CONCLUSIONS AND RELEVANCE In this family, microphthalmia, microcephaly, intellectual disability, and short stature are associated with a mutation on the X chromosome in the HMGB3 gene. HMGB3 should be considered when performing genetic studies of patients with similar phenotypes.

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Genetic heterogeneity of syndromic X‐linked recessive microphthalmia‐anophthalmia: Is Lenz microphthalmia a single disorder?

Ng¹,

Hadley²,

Tifft³

et al. 2002

Am. J. Med. Genet.

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Nonsyndromic congenital microphthalmia or anophthalmia is a heterogeneous malformation with autosomal dominant, autosomal recessive, and X-linked modes of inheritance. Lenz microphthalmia syndrome comprises microphthalmia with mental retardation, malformed ears, skeletal anomalies, and is inherited in an X-linked recessive pattern. Prior studies have shown linkage of both isolated (or nonsyndromic) anophthalmos (ANOP1, [MIM 301590]) and Lenz syndrome [MIM 309800] to Xq27-q28. Nonsyndromic colobomatous microphthalmia [MIM 300345] has been linked to Xp11.4-Xq11.1. We describe a five-generation African-American family with microphthalmia or anophthalmia, mental retardation, and urogenital anomalies, in an X-linked recessive inheritance pattern, consistent with Lenz syndrome. Initial linkage analysis with microsatellite markers excluded the region in Xq27-q28 previously reported as a candidate region for ANOP1 [MIM 301590]. An X-chromosome scan revealed linkage to a 10-cM region between markers DXS228 and DXS992 in Xp11.4-p21.2. Multipoint analysis gave a maximum LOD score of 2.46 at marker DXS993. These data show that X-linked recessive syndromic microphthalmia exhibits genetic heterogeneity. In addition, it suggests that Lenz microphthalmia syndrome, previously thought to be a single disorder, may represent an amalgam of two distinct disorders.

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Manifestations in four males with and an obligate carrier of the Lenz microphthalmia syndrome

Cited by 34 publications

References 12 publications

A splice donor mutation inNAA10results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome

A splice donor mutation inNAA10results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome

Identification of anHMGB3Frameshift Mutation in a Family With an X-linked Colobomatous Microphthalmia Syndrome Using Whole-Genome and X-Exome Sequencing

Genetic heterogeneity of syndromic X‐linked recessive microphthalmia‐anophthalmia: Is Lenz microphthalmia a single disorder?

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