Precocious chondrocyte differentiation disrupts skeletal growth in Kabuki syndrome mice

Fahrner, Jill A.; Lin, Wan Ying; Riddle, Ryan C.; Boukas, Leandros; DeLeon, Valerie B.; Chopra, Sheetal; Lad, Susan E.; Luperchio, Teresa Romeo; Hansen, Kasper D.; Björnsson, Hans T.

doi:10.1172/jci.insight.129380

Cited by 35 publications

(64 citation statements)

References 69 publications

(84 reference statements)

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“…Herein, we detail the immunological phenotype of a haploinsufficient mouse model of KS (Kmt2d 1/bGeo mice) in which the enzymatic domain of 1 copy of Kmt2d has been replaced with a bGeo cassette. This mouse reliably models KS phenotypes, [8][9][10] and we show that many of the immune phenotypes observed in patients (IgA deficiency, impaired response to vaccination, and splenomegaly) are also recapitulated in these mice. [11][12][13] We also uncover novel phenotypes including decreased size and numbers of Peyer patches (PPs), as well as abnormalities of the peritoneal cavity, bone marrow, and intestinal B-cell/plasma-cell compartments.…”

mentioning

confidence: 68%

Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome

Pilarowski

Cazares

Zhang

et al. 2020

Journal of Allergy and Clinical Immunology

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Background: Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. Objective: We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). Methods: We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d 1/bGeo) mouse model and validated select findings in a patient with KS. Results: Compared with wild-type littermates, Kmt2d 1/bGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d 1/bGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d 1/bGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. Conclusions: Kmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA 1 plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency.

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confidence: 68%

Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome

Pilarowski

Cazares

Zhang

et al. 2020

Journal of Allergy and Clinical Immunology

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“…A recent study of the skeletal phenotype in a KS-1 mouse model indicated that Kmt2d haploinsufficient mice have precocious chondrocyte differentiation and disrupted skeletal formation [135]. The mice have bowing of the ventral aspect of the skull and shortened long bones compared to wild-type controls, findings which recapitulate aspects of the human disease phenotype.…”

Section: Craniofacial Developmentmentioning

confidence: 95%

KMT2C/D COMPASS complex-associated diseases [KCDCOM-ADs]: an emerging class of congenital regulopathies

et al. 2020

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The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically active scaffold proteins that form the core of nuclear regulatory structures known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). These evolutionarily conserved proteins regulate DNA promoter and enhancer elements, modulating the activity of diverse cell types critical for embryonic morphogenesis, central nervous system development, and post-natal survival. KMT2C/D COMPASS complexes and their binding partners enhance active gene expression of specific loci via the targeted modification of histone-3 tail residues, in general promoting active euchromatic conformations. Over the last 20 years, mutations in five key COMPASS complex genes have been linked to three human congenital syndromes: Kabuki syndrome (type 1 [KMT2D] and 2 [KDM6A]), Rubinstein-Taybi syndrome (type 1 [CBP] and 2 [EP300]), and Kleefstra syndrome type 2 (KMT2C). Here, we review the composition and biochemical function of the KMT2 complexes. The specific cellular and embryonic roles of the KMT2C/D COMPASS complex are highlight with a focus on clinically relevant mechanisms sensitive to haploinsufficiency. The phenotypic similarities and differences between the members of this new family of disorders are outlined and emerging therapeutic strategies are detailed.

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“…KS mice phenotypes are comprised of skeletal growth retardation and decreased length and weight as a cause of shortened long bones [ 30 ]. These findings are also seen in KS patients [ 31 ].…”

Section: Growth and Endocrinologymentioning

confidence: 99%

“…Abnormal SOX9 expression (for instance, as a result of KMT2D variant) prevents the differentiation of chondrocytes into osteoblasts, ultimately causing too many chondrocytes and too few osteoblasts in the skeletal system. This probably causes improper growth, specifically growth retardation in KS (shortening of long bones and ineffective bone formation) [ 30 ].…”

Section: Growth and Endocrinologymentioning

confidence: 99%

Kabuki Syndrome—Clinical Review with Molecular Aspects

Boniel

Sztefko

Śmigiel

et al. 2021

Genes

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Kabuki syndrome (KS) is a rare developmental disorder principally comprised of developmental delay, hypotonia and a clearly defined dysmorphism: elongation of the structures surrounding the eyes, a shortened and depressed nose, thinning of the upper lip and thickening of the lower lip, large and prominent ears, hypertrichosis and scoliosis. Other characteristics include poor physical growth, cardiac, gastrointestinal and renal anomalies as well as variable behavioral issues, including autistic features. De novo or inherited pathogenic/likely pathogenic variants in the KMT2D gene are the most common cause of KS and account for up to 75% of patients. Variants in KDM6A cause up to 5% of cases (X-linked dominant inheritance), while the etiology of about 20% of cases remains unknown. Current KS diagnostic criteria include hypotonia during infancy, developmental delay and/or intellectual disability, typical dysmorphism and confirmed pathogenic/likely pathogenic variant in KMT2D or KDM6A. Care for KS patients includes the control of physical and psychomotor development during childhood, rehabilitation and multi-specialist care. This paper reviews the current clinical knowledge, provides molecular and scientific links and sheds light on the treatment of Kabuki syndrome individuals.

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Precocious chondrocyte differentiation disrupts skeletal growth in Kabuki syndrome mice

Cited by 35 publications

References 69 publications

Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome

Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome

KMT2C/D COMPASS complex-associated diseases [KCDCOM-ADs]: an emerging class of congenital regulopathies

Kabuki Syndrome—Clinical Review with Molecular Aspects

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