A Novel Homozygous Truncating Mutation in LAMB2 Gene in a Chinese Uyghur Patient With Severe Phenotype Pierson Syndrome

Objective: Pierson syndrome (OMIM 609049) is a rare autosomal recessive disorder characterized by congenital nephrotic syndrome and complex ocular abnormalities. Severe renal symptoms had be associated with truncating mutations. Few Chinese patients from diverse ethnic background had been evaluated and reported with this syndrome. Here we report the first Uyghur patient with typical Pierson syndrome phenotypes and a novel pathogenic homozygous variant in LAMB2 gene.Method: A thirty-nine-day old Uyghur girl was born to consanguineous parents, the girl presented with general edema, severe hypotonia and bilateral microcoria. Laboratory tests revealed severe proteinuria, microscopic haematuria, hypoalbuminaemia. By the age of 74 days, she died of renal failure and respiratory infection. We detected on mutations of LAMB2 gene by the sanger sequencing.Result:Sanger sequencing detected a homozygous 2-bp deletion (c.2044_2045insTT/p.Cys682Phefs*13) in the exon 16 of LAMB2 gene. Both parents are heterozygous carriers.Conclusion: We reported the first Uyghur case of LAMB2 gene homozygous mutation leading to severe phenotype Pierson syndrome. The clinical presentation of the patient and the novel pathogenic variant detected in this patient added to the overall knowledge of this rare condition

The complete mitochondrial genome sequence of Lepus tibetanus pamirensis

Lepus tibetanus pamirensis distributes only in the Pamir Plateau under a harsh environment with high attitude, cold and dry climates. The complete mitochondrial genome of the hare was determined (accession number MN539746) in a total length of 16,753 bp. The overall base composition of L. t. pamirensis mitogenome is 31.6% for A, 25.7% for C, 13.3% for G and 29.5% for T. It has the common characteristic with other mammals in regard to genome structure and gene arrangement. Based on published complete mitogenome sequences of lagomorphs, the phylogenetic tree suggested that L. t. pamirensis is closely related to L. yarkandensis and has far relationship with L. capensis. Our results would provide useful information for further study on conservation genetics and evolution of this hare species

Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish.

We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences

Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish

International audienceWe report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 ( MAP4K4 ). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences