The first patient with a pure 1p36 microtriplication associated with severe clinical phenotypes

Xu, Fang; Zhang, Yanan; Cheng, Dehua; Tan, Ke; Zhong, Chang-gao; Lu, Guangxiu; Lin, Ge; Tan, Yue‐Qiu

doi:10.1186/s13039-014-0064-9

Cited by 10 publications

(12 citation statements)

References 21 publications

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“…Analysis of PANK4 expression and structure in affected family members may shed light on this issue. PANK4 was found to be expressed in blood (Xu et al., ), and we found that the expression in the blood of our cataract patients was decreased. This result demonstrated that the mutation in the PANK4 gene influences the protein expression.…”

Section: Discussionsupporting

confidence: 57%

A novel mutation ofPANK4causes autosomal dominant congenital posterior cataract

et al. 2019

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Though many mutations have been identified to be associated with the occurrence of congenital cataract, pathogenic loci in some affected families are still unknown. Clinical data and genomic DNA were collected from a four‐generation Chinese family. Candidate mutations were independently verified for cosegregation in the whole pedigree. Linkage analysis showed that the disease‐causing mutation was located between 1p36.21 and 1p36.33. Analysis of the whole‐exome sequencing data combined with linkage analysis identified a novel pathogenic variant (g.2451906C>T) at intron 4 of Pantothenate kinase 4 (PANK4 protein, PANK4 gene) in 1p36.32|606162. This variant showed complete cosegregation with the phenotype in the pedigree. The mutation was not detected in 106 normal controls nor in 40 sporadic congenital cataract patients. The mutation was demonstrated to significantly reduce the expression of the PANK4 protein level in the blood of cataract patients than that in normal individuals by ELISA. Pank4−/− mice showed a cataract phenotype with increased numbers of apoptotic lens epithelial cells, fiber cell aggregation, and significant mRNA variation of crystallin family members. Thus, the association of a new entity of an autosomal dominant cataract with mutations in PANK4, which influences cell proliferation, apoptosis of lens epithelial cells, crystallin abnormalities, and fiber cell derangement, subsequently induces cataract.

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Section: Discussionsupporting

confidence: 57%

A novel mutation ofPANK4causes autosomal dominant congenital posterior cataract

et al. 2019

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“…A cellular function for HsPANK4 is apparent from two studies that identify congenital disease associated with amplification or reduction of PANK4 expression . In particular, reduced expression due to intronic mutation was causative for congenital cataracts in both humans and mice .…”

Section: Discussionmentioning

confidence: 99%

“…A cellular function for HsPANK4 is apparent from two studies that identify congenital disease associated with amplification or reduction of PANK4 expression. 49,50 In particular, reduced expression due to intronic mutation was causative for congenital cataracts in both humans and mice. 50 HsPANK4 has been reported to directly interact with LDHA, LDHB, HSP90AB1, MYBL2, TUBA1B, NUP133, and GCC1, 51 and these protein-protein interactions are candidates for PANK4 cellular activity.…”

Section: Discussionmentioning

confidence: 99%

Human pantothenate kinase 4 is a pseudo‐pantothenate kinase

et al. 2019

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Pantothenate kinase generates 4′‐phosphopantothenate in the first and rate‐determining step of coenzyme A (CoA) biosynthesis. The human genome encodes three well‐characterized and nearly identical pantothenate kinases (PANK1‐3) plus a putative bifunctional protein (PANK4) with a predicted amino‐terminal pantothenate kinase domain fused to a carboxy‐terminal phosphatase domain. Structural and phylogenetic analyses show that all active, characterized PANKs contain the key catalytic residues Glu138 and Arg207 (HsPANK3 numbering). However, all amniote PANK4s, including human PANK4, encode Glu138Val and Arg207Trp substitutions which are predicted to inactivate kinase activity. Biochemical analysis corroborates bioinformatic predictions—human PANK4 lacks pantothenate kinase activity. Introducing Glu138Val and Arg207Trp substitutions to the human PANK3 and plant PANK4 abolished their robust pantothenate kinase activity. Introducing both catalytic residues back into human PANK4 restored kinase activity, but only to a low level. This result suggests that epistatic changes to the rest of the protein already reduced the kinase activity prior to mutation of the catalytic residues in the course of evolution. The PANK4 from frog, an anamniote living relative encoding the catalytically active residues, had only a low level of kinase activity, supporting the view that HsPANK4 had reduced kinase activity prior to the catalytic residue substitutions in amniotes. Together, our data show that human PANK4 is a pseudo‐pantothenate kinase—a catalytically deficient variant of the catalytically active PANK4 found in plants and fungi. The Glu138Val and Arg207Trp substitutions in amniotes (HsPANK3 numbering) completely deactivated the pantothenate kinase activity that had already been reduced by prior epistatic mutations.

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“…Giannikou et al 64 reported two individuals with relatively small, de novo, isolated terminal 1p36 duplications (chr1:1–1,565,789 and chr1:1–1,565,607): a 6-month-old male with hypotonia and severe psychomotor delay and a 17-year-old male with growth hormone deficiency, short stature, psychomotor delay, and left ventricular hypertrophy. Subsequently, Xu et al 65 reported an 8-year-old female who carried four copies of approximately 5.28 Mb of the terminal region of 1p36. Her phenotypes included feeding difficulties in infancy, developmental delay, seizures, microcephaly, strabismus, hypertelorism, a low hairline, ear malformations, a broad nasal bridge, wide mouth, thick lips, and prominent incisors.…”

Section: P36 Copy Number Gainsmentioning

confidence: 99%

1p36 deletion syndrome: an update

Jordan¹,

Zaveri²,

Scott³

2015

TACG

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Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are the most common terminal deletions in humans. Medical problems commonly caused by terminal deletions of 1p36 include developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, distinctive facial features, brain anomalies, orofacial clefting, congenital heart defects, cardiomyopathy, and renal anomalies. Although 1p36 deletion syndrome is considered clinically recognizable, there is significant phenotypic variation among affected individuals. This variation is due, at least in part, to the genetic heterogeneity seen in 1p36 deletions which include terminal and interstitial deletions of varying lengths located throughout the 30 Mb of DNA that comprise chromosome 1p36. Array-based copy number variant analysis can easily identify genomic regions of 1p36 that are deleted in an affected individual. However, predicting the phenotype of an individual based solely on the location and extent of their 1p36 deletion remains a challenge since most of the genes that contribute to 1p36-related phenotypes have yet to be identified. In addition, haploinsufficiency of more than one gene may contribute to some phenotypes. In this article, we review recent successes in the effort to map and identify the genes and genomic regions that contribute to specific 1p36-related phenotypes. In particular, we highlight evidence implicating MMP23B, GABRD, SKI, PRDM16, KCNAB2, RERE, UBE4B, CASZ1, PDPN, SPEN, ECE1, HSPG2, and LUZP1 in various 1p36 deletion phenotypes.

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The first patient with a pure 1p36 microtriplication associated with severe clinical phenotypes

Cited by 10 publications

References 21 publications

A novel mutation ofPANK4causes autosomal dominant congenital posterior cataract

A novel mutation ofPANK4causes autosomal dominant congenital posterior cataract

Human pantothenate kinase 4 is a pseudo‐pantothenate kinase

1p36 deletion syndrome: an update

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