Mother‐to‐daughter transmission of Kenny–Caffey syndrome associated with the recurrent, dominant <i><scp>FAM111A</scp></i> mutation p.<scp>Arg569His</scp>

Nikkel, Sarah M.; Ahmed, Abu Saleh; Smith, Amanda; Marcadier, Julien L.; Bulman, Dennis E.; Boycott, Kym M.

doi:10.1111/cge.12290

Cited by 30 publications

(35 citation statements)

References 7 publications

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“…Because FAM111A exhibits cell cycledependent expression (45), and as we have shown here is induced by IFN, IRF2 might not be needed for induction under some conditions. Mutations of FAM111A cause Kenny-Caffey syndrome (46,47), hypoparathyriodism, and impaired skeletal development (48). Interestingly, FAM111A is a host restriction factor for an SV40 mutant (34).…”

Section: Discussionmentioning

confidence: 99%

Triad of human cellular proteins, IRF2, FAM111A, and RFC3, restrict replication of orthopoxvirus SPI-1 host-range mutants

Panda

Fernández

Lal

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Viruses and their hosts can reach balanced states of evolution ensuring mutual survival, which makes it difficult to appreciate the underlying dynamics. To uncover hidden interactions, virus mutants that have lost defense genes may be used. Deletion of the gene that encodes serine protease inhibitor 1 (SPI-1) of rabbitpox virus and vaccinia virus, two closely related orthopoxviruses, prevents their efficient replication in human cells, whereas certain other mammalian cells remain fully permissive. Our highthroughput genome-wide siRNA screen identified host factors that prevent reproduction and spread of the mutant viruses in human cells. More than 20,000 genes were interrogated with individual siRNAs and those that prominently increased replication of the SPI-1 deletion mutant were subjected to a secondary screen. The top hits based on the combined data-replication factor C3 (RFC3), FAM111A, and interferon regulatory factor 2 (IRF2)-were confirmed by custom assays. The siRNAs to RFC1, RFC2, RFC4, and RFC5 mRNAs also enhanced spread of the mutant virus, strengthening the biological significance of the RFC complex as a host restriction factor for poxviruses. Whereas association with proliferating cell nuclear antigen and participation in processive genome replication are common features of FAM111A and RFC, IRF2 is a transcriptional regulator. Microarray analysis, quantitative RT-PCR, and immunoblotting revealed that IRF2 regulated the basal level expression of FAM111A, suggesting that the enhancing effect of depleting IRF2 on replication of the SPI-1 mutant was indirect. Thus, the viral SPI-1 protein and the host IRF2, FAM111A, and RFC complex likely form an interaction network that influences the ability of poxviruses to replicate in human cells.poxviruses | host range | DNA replication factors | interferon regulatory factor | RNAi screen

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Section: Discussionmentioning

confidence: 99%

Triad of human cellular proteins, IRF2, FAM111A, and RFC3, restrict replication of orthopoxvirus SPI-1 host-range mutants

Panda

Fernández

Lal

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The identified cases from the two above-mentioned series were de novo mutations [4, 15]. However, the earliest description of KCS described a mother-to-son transmission [16] and this has been further elaborated in a second case of mother-to-daughter transmission of the same mutation with both mother and child affected [17] consistent with an autosomal dominant inheritance.…”

Section: Discussionmentioning

confidence: 99%

Short stature and hypoparathyroidism in a child with Kenny-Caffey syndrome type 2 due to a novel mutation in FAM111A gene

Abraham

Dong

Tang

et al. 2017

Int J Pediatr Endocrinol

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BackgroundHypoparathyroidism in children is a heterogeneous group with diverse genetic etiologies. To aid clinicians in the investigation and management of children with hypoparathyroidism, we describe the phenotype of a 6-year-old child with hypoparathyroidism and short stature diagnosed with Kenny-Caffey syndrome (KCS) Type 2 and the subsequent response to growth hormone (GH) treatment.Case presentationThe proband presented in the neonatal period with hypocalcemic seizures secondary to hypoparathyroidism. Her phenotype included small hands and feet, hypoplastic and dystrophic nails, hypoplastic mid-face and macrocrania. Postnatal growth was delayed but neurodevelopment was normal. A skeletal survey at 2 years of age was suggestive of KCS Type 2 and genetic testing revealed a novel de novo heterozygous mutation c.1622C > A (p.Ser541Tyr) in FAM111A. At 3 years and 2 months, her height was 80cms (SDS −3.86). She had normal overnight GH levels. GH therapy was commenced at a dose of 4.9 mg/m2/week for her short stature and low height velocity of 5cms/year. At the end of the first and second years of GH treatment, height velocity was 6.5cms/year and 7.2cms/year, respectively with maximal dose of 7.24 mg/m2/week.ConclusionThis case highlights the phenotype and the limited response to GH in a child with genetically proven KCS type 2. Long-term registries monitoring growth outcomes following GH therapy in patients with rare genetic conditions may help guide clinical decisions regarding the use and doses of GH in these conditions.

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“…3,6 KCS2 (OMIM 127000), on the other hand, is autosomal dominant due to heterozygous variants in FAM111A, a gene that seems crucial for parathyroid hormone regulation, calcium homeostasis, and normal bone and growth development. 3,5,7 We report a female patient with a hotspot variant in FAM111A. Her clinical findings are unusual in that it include ophthalmologic manifestations and global developmental delays.…”

Section: Introductionmentioning

confidence: 92%

“…2 KCS is clinically characterized by growth retardation, delay in bone maturation, cortical thickening of the long bones and medullary stenosis, delayed closure of fontanelle, ophthalmic and dental abnormalities, hypocalcemia secondary to hypoparathyroidism, and convulsion associated with hypocalcemia. 1,[3][4][5] KCS is classified according to clinical features and mode of inheritance into two types: Kenny-Caffey syndrome type 1 (KCS1) is characterized by delays in cognitive development, while Kenny-Caffey syndrome type 2 (KCS2) manifests classically with a normal intelligence. 3 As for their pattern of inheritance, KCS1 (OMIM 244460) is classified as an autosomal recessive syndrome and is associated with homozygous or compound heterozygous variants in TBCE.…”

Section: Introductionmentioning

confidence: 99%

Ophthalmologic Impairment and Intellectual Disability in a Girl Presenting Kenny-Caffey Syndrome Type 2

et al. 2020

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Kenny-Caffey syndrome (KCS) is a rare genetic condition characterized by growth retardation, bone abnormalities, and hypoparathyroidism. Herein, we report an unusual case of a 10-year-old girl with Kenny-Caffey syndrome type 2 (KCS2) presenting with vision impairment-suspected maculopathy and intellectual disability. Endocrine evaluation showed low calcium and high phosphorus plasma levels. Radiographic evaluation revealed short metacarpal bones and delayed bone age. Sequencing analysis showed a missense variant in FAM111A (R569H), unidentified in her parents. Better understanding of potential neurological and ophthalmological findings in KCS2 patients is important to improve quality of life of these patients as usually they exhibit long survival.

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Mother‐to‐daughter transmission of Kenny–Caffey syndrome associated with the recurrent, dominant FAM111A mutation p.Arg569His

Cited by 30 publications

References 7 publications

Triad of human cellular proteins, IRF2, FAM111A, and RFC3, restrict replication of orthopoxvirus SPI-1 host-range mutants

Triad of human cellular proteins, IRF2, FAM111A, and RFC3, restrict replication of orthopoxvirus SPI-1 host-range mutants

Short stature and hypoparathyroidism in a child with Kenny-Caffey syndrome type 2 due to a novel mutation in FAM111A gene

Ophthalmologic Impairment and Intellectual Disability in a Girl Presenting Kenny-Caffey Syndrome Type 2

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