Abstract:
:Glycosylphophatidylinositol (GPI)-anchored proteins play important roles in many biological processes, and mutations affecting proteins involved in the synthesis of the GPI anchor are reported to cause a wide spectrum of intellectual disabilities (IDs) with characteristic additional phenotypic features. Here, we describe a total of five individuals (from three unrelated families) in whom we identified mutations in PGAP3, encoding a protein that is involved in GPI-anchor maturation. Three siblings in a consanguineous Pakistani family presented with profound developmental delay, severe ID, no speech, psychomotor delay, and postnatal microcephaly. A combination of autozygosity mapping and exome sequencing identified a 13.8 Mb region harboring a homozygous c.275G>A (p.Gly92Asp) variant in PGAP3 region 17q11.2-q21.32. Subsequent testing showed elevated serum alkaline phosphatase (ALP), a GPI-anchored enzyme, in all three affected children. In two unrelated individuals in a cohort with developmental delay, ID, and elevated ALP, we identified compound-heterozygous variants c.439dupC (p.Leu147Profs(∗)16) and c.914A>G (p.Asp305Gly) and homozygous variant c.314C>G (p.Pro105Arg). The 1 bp duplication causes a frameshift and nonsense-mediated decay. Further evidence supporting pathogenicity of the missense mutations c.275G>A, c.314C>G, and c.914A>G was provided by the absence of the variants from ethnically matched controls, phylogenetic conservation, and functional studies on Chinese hamster ovary cell lines. Taken together with recent data on PGAP2, these results confirm the importance of the later GPI-anchor remodelling steps for normal neuronal development. Impairment of PGAP3 causes a subtype of hyperphosphatasia with ID, a congenital disorder of glycosylation that is also referred to as Mabry syndrome.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Howard MF,Murakami Y,Pagnamenta AT,Daumer-Haas C,Fischer B,Hecht J,Keays DA,Knight SJ,Kölsch U,Krüger U,Leiz S,Maeda Y,Mitchell D,Mundlos S,Phillips JA 3rd,Robinson PN,Kini U,Taylor JC,Horn D,Kinoshita T,Krawitz Pdoi
10.1016/j.ajhg.2013.12.012subject
Has Abstractpub_date
2014-02-06 00:00:00pages
278-87issue
2eissn
0002-9297issn
1537-6605pii
S0002-9297(13)00582-Xjournal_volume
94pub_type
杂志文章abstract::More than 270 million people worldwide have hearing loss that affects normal communication. Although astonishing progress has been made in the identification of more than 50 genes for deafness during the past decade, the majority of deafness genes are yet to be identified. In this study, we mapped a previously unknown...
journal_title:American journal of human genetics
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journal_title:American journal of human genetics
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更新日期:1993-06-01 00:00:00
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journal_title:American journal of human genetics
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更新日期:1994-11-01 00:00:00
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更新日期:1983-05-01 00:00:00
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pub_type: 杂志文章
doi:10.1086/423903
更新日期:2004-09-01 00:00:00
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journal_title:American journal of human genetics
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更新日期:2005-12-01 00:00:00
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journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1987-04-01 00:00:00
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journal_title:American journal of human genetics
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doi:
更新日期:1996-11-01 00:00:00
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journal_title:American journal of human genetics
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doi:
更新日期:1993-01-01 00:00:00
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journal_title:American journal of human genetics
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journal_title:American journal of human genetics
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journal_title:American journal of human genetics
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更新日期:1995-12-01 00:00:00
abstract::Diabetes mellitus and neurodegeneration are common diseases for which shared genetic factors are still only partly known. Here, we show that loss of the BiP (immunoglobulin heavy-chain binding protein) co-chaperone DNAJC3 leads to diabetes mellitus and widespread neurodegeneration. We investigated three siblings with ...
journal_title:American journal of human genetics
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journal_title:American journal of human genetics
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doi:
更新日期:1993-07-01 00:00:00
abstract::Although a considerable number of papers have been published dealing with the frequency and variety of genetic and nongenetic limb defects in newborns and to a lesser extent among embryos, little has been published about the range of limb defects among spontaneously aborted middle and late-term fetuses. This study rep...
journal_title:American journal of human genetics
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更新日期:1983-05-01 00:00:00
abstract::A model is considered to calculate effects of genetic drift on the expected proportion of new mutants amongst males affected by a sex-linked recessive lethal. We show how to relate the number of cases of the disorder in males to the expected deviations from the deterministic value of the proportion of new mutants. For...
journal_title:American journal of human genetics
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更新日期:1979-03-01 00:00:00
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journal_title:American journal of human genetics
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